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7: Host Defenses - Biology

7: Host Defenses - Biology


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Reading assignment: Belk’s Biology p 478-479 (non-specific defenses) and p 479-487 (specfic defenses)

Note: (Warning?) Host defenses are complicated and amazing, worthy of a course alone. It is easy to be overwhelmed by the amount of info in this section.

  • At the start of non-specific defenses and specific immunity , a 2-3 page “overview” is used to introduce the topic and to provide a “roadmap” of the most important concepts.
  • The overview is followed by study guide questions.
  • Following the study guide questions are expanded notes for those who wish to explore more details.

Overview host defenses

1. Nonspecific defenses –first line of defenses

  1. Surface defenses: skin, mucous membranes
  2. Interior defenses: inflammation, phagocytosis, fever, complement, interferon, NK cells

2. Specific defenses-second line of defenses if non-specific defenses fail

  1. Humoral: antibody mediated defenses against extracellular pathogens and toxins
  2. CMI: cell mediated immunity against intracellular pathogens

Overview: Host non-specific defenses against microbial pathogens

I. Nonspecific surface defenses: skin and mucous membranes

A. Skin:

1. tightly packed cells prevent movement of microbes into deeper layers

2. dry: inhibits microbial growth

3. low pH; fatty acids inhibits microbial growth

4. keratin: increases strength of skin cells

5. normal microbiota: competition for attachment sites/nutrients, production of inhibitory bacteriocins

6. lysozyme: enzyme which breaks down bacterial cell walls

7. Any damage to skin (cuts, bites, burns) greatly decreases protective function of skin, may lead to infection

B. Mucous Membranes: delicate, moist cells lining gastrointestinal tract, respiratory, genital, urinary tracts, covered by sticky blanket of mucous. Control movement of substances into and out body.

1. mucin: “sticky blanket” traps invading microbes

2. flushing action of fluids, solid materials, removes microbes

3. lysozyme breaks down bacterial cell walls

4. normal microbiota: competition, bacteriocins, lactic acid inhibits pathogens

5. mucociliary escalator/ apparatus of respiratory tract, oviducts

-cold, smoking inhibits function of respiratory mucociliary escalator

-chronic infection of oviducts causes scarring, Pelvic Inflammatory Disease (PID), ectopic pregnancy, infertility

Overview: Host non-specific defenses against microbial pathogens, continued

IV. Nonspecific interior defenses

A. Inflammation

1. inflammatory mediators

-vasodilation

-increase capillary permeability

-pain receptors

2. signs/symptoms

-heat/hyperthermia

-redness/erythema

-swelling/edema

-pain

3. advantages/disadvantages

B. Phagocytosis

1. “professional” phagocytic cells: monocytes/macrophages and neutrophils

2. steps in phagocytosis

-chemotaxis

-contact and attachment to pathogen

-phagosome formation

-lysosome fusion with phagosome

-hydrolytic enzymes destroy pathogen

-myeloperoxidase activated with production of reactive oxygen intermediates, superoxide radicals, hydrogen peroxide, hypochlorous chloride

3. evasion of phagocytic killing by pathogens: capsules, leukocidins, escape from phagosome, natural resistance to hydrolytic enzymes

C. Fever

1. pyrogens cause fever

-exogenous pyrogen: e.g. bacterial ex lipid A of endotoxin

-endogenous pyrogen; WBC release interleukin-1 (IL-1)

-triggers anterior hypothalamus to synthesize prostaglandinns

-cause thermostat “resetting”-->fever

2. advantages/disadvantages

D. Complement

The “complement system” is a number of host proteins which normally circulate in an inactive state. Microbial substances can activate the complement system.

What are advantages of the complement system? Activated complement proteins can:

1. act as inflammatory mediators (increase blood flow, phagocytosis, etc)

2. act as “chemotaxins”, help guide phagocytes to invading microbes.

3. act as opsonins (coat pathogen to make pathogen “sticky”; consequently phagocytic cells can attach easier, increases phagocytic killing of pathogen)

4. MAC=membrane attack complex, complement protein form holes in membrane/envelopes of pathogens

E. Interferon: trigger production of “antiviral proteins” which inhibit viral replication in host cells

Study guide questions non-specific host defenses

1. Non-specific defenses of the host are the first lines of defense against invading pathogens. There are 2 lines of non-specific defenses listed below. Provide specific examples of each

a. non-specific surface defenses:

b. non-specific interior defenses:

2. What role does your normal microbiota, the “commensal” microbes which colonize your skin and mucous membranes play in non-specific surface defenses?

-how can taking “broad spectrum” antibiotics lower your non-specific surface defenses?

3. How could a pathogen “defeat” or “pass through” non-specific surface defenses?

Non-specific interior defenses

4. -What is inflammation?

-What causes inflammation?

-What are 4 signs of inflammation?

5. What are the advantages of inflammation?

6. Are there disadvantages to chronic inflammation?

7. What is phagocytosis?

a. Which leukocytes/white blood cells/WBC are called “professional phagocytes”?

b. Which of the phagocytes is the “first responder”?

c. describe the steps involved in the phagocytic killing of a microbe

8. What is fever?

a. what triggers fever production? Examples of pyrogens?

b. what are the advantages of fever production

c. What are “antipyretics”?

9. What is the complement system?

a. How is the complement system “activated”?

b. What are 3-4 advantages of complement activation?

-what is/are:

i. inflammatory mediators

ii. chemotactic factors

iii. opsonins

iv. MAC/ “Membrane Attack Complex”

10. What are interferons?

a. What triggers interferon production?

b. How do interferons protect cells against viral infections?

11. Why does smoking increase your risk for respiratory tract infections?

12.. Why will people frequently suffer from “yeast/Candida albicans” infections of mouth, vagina or anus following “broad spectrum” antibiotic therapy?

13. Why will many people develop “bacterial cystitis” following urinary catheterization?

Why may bacterial cystitis lead to kidney infections?

expanded notes!

Non-specific defenses of hosts against microbial pathogens: expanded notes

Overview of non-specific host defenses

1. Always present/active (“constitutive”)

2. Active against a wide-range of potential pathogens= “non-specific”

3. First lines of defense against invading microbes

4. 2 levels of nonspecific defenses

a. surface defenses

i. skin

ii. mucous membranes

b. interior defenses

i. inflammation

ii. phagocytosis

iii. fever

iv. complement activation

v. interferons

Surface non-specific defenses

1. skin: made up of multiple layers of tough keratinized epithelial cells held closely together by “tight junctions” and “intercellular cement” rich in hyaluronic acid. Features of skin which contributes to its ability to protect host from invading microbes include the following:

  • physical barrier: multiple layers of skin cells create a barrier, deeper layers of skin cells cemented tightly together (keratin produced by skin cells is a very strong protein thus adds to strength of barrier), consequently microbes can’t invade deeper into more delicate tissues
  • dry: many microbes require water rich environments to grow
  • acidic: fatty acids inhibit many microbes
  • sweat: salt in sweat inhibits many microbes
  • normal microbiota (skin mutualists and commensals which grow on skin without causing harm to host). Normal microbiota block attachment of invading pathogens, compete for living space and nutrients. Some normal microbiota produce inhibitory waste products e.g. lactic acid, which decrease growth of potential pathogens
  • sloughing skin: top layers of skin continuously sloughed, “falling off”. Pathogens attached to these layers are thus lost from host.

2. mucous membranes: delicate linings of mouth, gastrointestinal tract, respiratory tract, genital tract, urinary tract, eyes. Mucous membranes are made up of non-keratinized epithelial cells and mucous producing cells. Cells of the mucous membranes are covered in a moist, sticky mucous blanket. Features of mucous membranes which contribute to their ability to prevent colonization by potential pathogens include:

a. sticky mucous blanket: the mucous blanket acts as a “trap” for invading pathogens, and physically prevents the ability of some pathogens from reaching and binding to underlying host cells. Normally the mucous blanket is continually removed from the host, thus expelling the trapped pathogens before they can cause serious disease

b. ciliated cells of upper respiratory tract and oviducts and the “mucociliary escalator”: mucous membranes of respiratory tract and oviducts contain “ciliated epithelial cells”. Ciliated cells have tiny hair like protrusions (cilia) which can move in wavelike motions. When these cilia beat in unison, they can move substances across the surface of the ciliated cells. The ciliated cells can move mucous blankets out of the host or create currents to direct ovulated eggs toward the uterus. Damage to or loss of ciliated cells occurs in the respiratory tract as a consequence of smoking or viral infections; consequently there is a much higher risk of bacterial pneumonia. Likewise when women experience long-term genital tract infections, the ciliated cells of their oviducts are destroyed. Consequently the women can experience ectopic pregnancies, sterility and PID or Pelvic Inflammatory Disease.

-normal microbiota: some mucous membranes (ex mouth, intestine, vagina, nose)are colonized by microbial mutualists and commensals which usually do not cause harm to the host . As with skin microbiota, these normal inhabitants can block attachment of pathogens to host cells, compete for nutrients and produce waste products which can inhibit the growth of many microbial pathogens.

-taking “broad spectrum antibiotics”, those which kill a wide-range of bacteria both beneficial and pathogenic, can cause lower one’s natural defenses against potential pathogens. e.g. women taking antibiotics for bacterial bladder infections/cystitis frequently develop “secondary” vaginal yeast infections with the yeast Candida albicans as a consequence of the killing of their “good” normal microbiota.

-“flushing action”- the movement of liquids or solids over the surfaces of mucous membranes helps to wash/flush away potential pathogens. Examples include movement of food/water through gastrointestinal tract, defecation, urination, lacrimation/”crying”, movement of nasal secretions/mucous through respiratory tract, movement of mucous secretions through genital tract

-additional chemicals found in body secretions: for example lysozyme (breaks down bacterial cell walls); bile (emulsifies microbes, has a detergent-like action on lipid rich membranes/envelopes)

Interior non-specific defenses

How can pathogens cross surface defenses?

Pathogens may bypass surface defenses when skin/mucous membranes are damaged (e.g. insect bites, wounds, burns, surgery). Microbes may also evolve strategies to avoid these surface defenses.

What happens if pathogens cross surface defenses?

Second line of non-specific defenses are activated, the interior (‘inside”) defenses: inflammation, phagocytosis by neutrophils and macrophages; fever; complement activation; interferon production

1. Inflammation: body’s response to any kind of damage including invasion by microbial pathogens

a. classical signs of inflammation= redness-heat-swelling-pain

-caused by release of substances called “inflammatory mediators” ( for example histamine)

b. The inflammatory mediators trigger the following changes (which in turn cause the classical signs of inflammation)

- “vasodilation”: blood vessel diameter increases so more blood flows to site of injury. Increased blood flow causes area to appear red and increases temperature/heat

-“increased capillary permeability”: vessels become “leakier” so fluid escapes from blood into surrounding tissues, causing the injured area to swell

c. pain: inflammatory mediators may act directly on pain receptors and/or swelling can contribute to sensation of pain

d. What does inflammation accomplish?

d. What does inflammation accomplish?

-By increasing blood flow to an injured area, inflammation increases delivery of protective white blood cells/leukocytes called “phagocytes” . First to arrive are phagocytic neutrophils, then later phagocytic macrophages.

-The phagocytes will “eat”/phagocytize invading pathogens and kill them hopefully before they can cause disease.

-The inflammatory mediators set-up a chemical concentration gradient which helps guide the phagocytes to “ground zero”, the site of pathogen invasion

  • The phagocytes use the chemical concentration gradient to guide their movements in a process called “chemotaxis

-Increased temperature may increase the killing activity of phagocytes

-Increased blood flow also increases deliver of nutrients, oxygen and other defensive substances to the injured site including complement and antibodies

-Vessel leakiness eases the ability of the phagocytes to leave the blood vessels (a process called emigration) and migrate into the invaded tissues

-Leaky vessels also increase delivery of substances which produce “fibrin clots” around the invading pathogens which will reduce their ability to spread into neighboring tissues

e. Are there any disadvantages to inflammation?

-chronic/long term inflammation can actually harm the host. Why?

-“sloppy feeding” phagocytes can dump hydrolytic enzymes onto host cells, causing host cell damage

-sufficient damage can cause loss of normal cells and replacement by fibrous connective tissue (“scar tissue”) with resulting loss of function of the tissue/organ

-inflammation can cause abnormal function of tissues/organs

2. Phagocytosis: literally means “cell eating”

-Many cells in the host can carry out “endocytosis’, bringing into the cell substances from outside in a membrane bound vesicle

-endocytosis involving liquids is called “pinocytosis”/cell drinking

-endocytosis involving large particles or other cells is called “phagocytosis”/cell eating

-only some cells in the body are called “professional phagocytes”. The function of professional phagocytes is to phagocytize (“eat”) and destroy invading pathogens (they may also play a role in triggering the specific immune responses we will discuss later)

Non-specific interior defenses: Phagocytosis, continued

Professional phagocytes include:

a. neutrophils: the “first responders” to microbial invasion., short-lived.

b. monocytes-macrophages: slower, but longer lived; often called the “garbage trucks” of the body. Also important in helping trigger specific immune responses

c. both neutrophils and macrophages are called “leukocytes” or white blood cells or WBC’s. They do not contain hemoglobin as do erythrocytes or red blood cells/RBC’s and thus appear “white”.

There are 3 other types of leukocytes (lymphocytes, eosinophils and basophils) which we will discuss later

Steps in phagocytosis

1. Chemotaxis: chemical gradients guide phagocytic cells to the site of microbial invasion

2. Attachment: phagocyte surface receptors must bind to surface molecules on pathogen

3. Phagosome formation: phagocyte pseudopodia (“false feet”, extensions of cytoplasmic membrane) wrap around pathogen and fuse, forming membrane bound vesicle around pathogen. This vesicle is called the phagosome (literally “eating body”). The pathogen is now within phagocyte.

-proton pumps in the phagosome membrane pump hydrogen ions into the phagosome, acidifying the inside

-the hydrogen ions/protons will help activate the hydrolytic enzymes in the next step….

4. Lysosome fusion with phagosome: A second membrane bound vesicle filled with hydrolytic enzymes then fuses with the phagosome, creating a “phagolysosome”. The hydrolytic enzymes are activated by the hydrogen ions.The hydrolytic enzymes start to “digest” the pathogen, breaking down the proteins, carbohydrates, lipids and nucleic acids; the pathogen is thus killed.

-nutrients will be absorbed by the phagocyte

5. Respiratory/oxidative burst triggered by activation of myeloperoxidase system: enzymes in the phagolysosome also generate superoxide anions, hydrogen peroxide and other toxic substances which will increase the likelihood of the pathogen’s destruction

6. Waste material is dumped via a process called “exocytosis”

Non-specific interior defenses, phagocytosis continued

Note: many pathogens have evolved ways to avoid/”outwit” one or more of the steps involved in phagocytosis, more later. Some pathogens require phagocytosis to successfully invade the host!

---------------------------------------------------------------

3. Fever production

Substances which trigger fever production are called “pyrogens” (literally “fire-makers”)

Microbial substances can act as pyrogens (exogenous pyrogens; exogenous=comes from outside). Microbial substances can cause host cells to release substances called endogenous pyrogens (endogenous: from within) such as Interleukin-1 IL-1. IL-1 travels to the brain’s hypothalamus and triggers a re-setting of the body’s thermostat. Consequently the brain triggers a number of adaptations to increase core body temperature e.g. shivering, vasoconstriction, behavioral changes (seeking warmth, dressing in more layers, covering self with blankets)

Why will increased body temperature help the host when invade by a pathogen?

Increased body temp has shown to :

-increase killing rate by phagocytes

-increase chemical killing of pathogens

-may decrease replication of some pathogens

-decrease iron absorption from intestine (some pathogens require iron)

Antipyretics are substance which reduce fevers; examples acetaminophen, aspirin, ibuprofen

------------------------------------------------------------

4. Complement activation1. inactive proteins synthesized by liver

2. 2 ways to activate complement

a. alternative pathway: contact with bacterial surface e.g. LPS

b. classicial pathway: antigen-antibody complexes activate (later; specific defenses)

c. both pathways lead to formation of

-C3a: inflammatory mediator

-C3b: opsonin

-and activation of the terminal pathway

3. Terminal pathway: results in formation of:

a. C5a: inflammatory mediator

b. ”MAC”: membrane attack complex

-creates pores in bacterial outer membrane/ any cell membrane-> osmotic lysis

4. cascade: series of reactions in which product of one reaction activates the next reaction.

5. amplification: each active product molecule activates many subsequent reactions so cascade expands/amplifies as it proceeds.

6. Results: inflammatory mediators, opsonins, chemotactic factors, “MAC”, membrane attack complex

-------------------------------------------

5. Interferons alpha and beta

Some viruses can trigger invaded host cells to produce alpha and beta interferon IFN. IFN’s trigger neighboring cells to make “AVPs”, antiviral proteins which can block replication of viruses.

Specific acquired immunity

Overview

Recall the body’s first line of defense are the non-specific defenses discussed earlier (skin, mucous membranes, inflammation, phagocytosis, complement activation and more).

-What happens if non-specific defenses are unable to halt infection by invading pathogens?

The body has a second, stronger line of defense called “specific, acquired” immunity. It is “specific” for the invading pathogen and “acquired” because it is only activated after the body is invaded by the pathogen (or after vaccination…more later).

Specific immunity has 2 branches:

1. humoral immunity= protection provided by antibodies or immunoglobulins

-humoral immunity offers protection against extracellular pathogens and toxins (toxins and pathogens found outside of host cells)

2. cell mediated immunity (“CMI”)= protection offered by T lymphocytes and activated macrophages

  • CMI offers protection against intracellular pathogens (ex viruses) (intracellular=within a cell)
  • CMI also offers protection against cancer cells, large eukaryotic pathogens such as worms and fungi
  • CMI is also responsible for transplant rejection

Specific Acquired immunity Overview; Humoral and Cell Mediated Immunity

  1. Antigens trigger specific immunity
  2. Humoral immunity is protection provided by antibodies/immunoglobulins. Antibody functions include:
    1. Neutralization: black attachment of pathogen or toxins to host cells
    2. Agglutination/clumping and precipitation
    3. Opsonization: coat pathogens to increase phagocytic killing
    4. Activation of MAC via complement
  3. Antibodies are synthesized by special B lymphocytes called plasma cells. Good antibody production requires T helper lymphocyte chemical “help”
  4. Primary immune responses are slow, low and short lived BUT memory cells are made agasint the pathogen antigens
  5. Secondary immune responses are faster, stronger and longer lasting than primary immune responses. Production of memory cells and secondary immune responses are the basis for vaccine protection against pathogens.
  6. Antibodies can protect against extracellular pathogens or toxins but cannot get inside cells. Cell Mediated Immunity ‘CMI” is used to protect against intracellular pathogens
  7. CMI against viruses: cytotoxic T lymphocytes target and kill virus infected cells
  8. CMI against facultative intracellular parasites of phagocytic cells: special T helper lymphocytes can activate phagocytes to enable them to kill bacterial intracellular parasites.
  9. HIV destroys T helper lymphocytes, the most important cells of the immune system. Without T helpers, neither humoral nor cell mediated immunity can function properly. When T helper lymphocytes decrease sufficiently, a person becomes immunocompromised (AIDS) and often dies from low virulence “opportunistic pathogens”.

Study guide Specific acquired Immunity

  1. How is specific immunity different from non-specific immunity? Does specific immunity have any disadvantages when compared with non-specific defenses?
  2. What is “immunological memory” and why is it important?
  3. What are antigens?
  4. What is humoral immunity?
  5. Describe 4 functions of antibodies
  6. Describe the structure of an antibody and different functional parts.
  7. Describe 5 antibody classes and functions (matching)
  8. Which cells make antibodies?
  9. Why are T helper lymphocytes important in antibody production?
  10. Which 3 types of cells are involved in “B dependent” antibody production?
  11. What are special challenges of “B independent antigens”? How have these problems been overcome? What are conjugate vaccines? Examples?
  12. Briefly describe the function of T cytotoxic lymphocytes in virus infections
  13. Briefly describe role of T helper lymphocytes in activation of macrophages.
  14. Why may HIV infections “cripple” a person’s immune system? What is the consequence, why?

Host Defense Mechanisms Against Infection

The skin usually bars invading microorganisms unless it is physically disrupted (eg, by arthropod vectors, injury, IV catheters, surgical incision). Exceptions include the following:

Human papillomavirus, which can invade normal skin, causing warts

Mucous membranes

Many mucous membranes are bathed in secretions that have antimicrobial properties (eg, cervical mucus, prostatic fluid, and tears containing lysozyme, which splits the muramic acid linkage in bacterial cell walls, especially in gram-positive organisms).

Local secretions also contain immunoglobulins, principally IgG and secretory IgA, which prevent microorganisms from attaching to host cells, and proteins that bind iron, which is essential for many microorganisms.

Respiratory tract

The respiratory tract has upper airway filters. If invading organisms reach the tracheobronchial tree, the mucociliary epithelium transports them away from the lung. Coughing also helps remove organisms. If the organisms reach the alveoli, alveolar macrophages and tissue histiocytes engulf them. However, these defenses can be overcome by large numbers of organisms, by compromised effectiveness resulting from air pollutants (eg, cigarette smoke), interference with protective mechanisms (eg, endotracheal intubation, tracheostomy), or by inborn defects (eg, cystic fibrosis).

Gastrointestinal tract

Gastrointestinal tract barriers include the acid pH of the stomach and the antibacterial activity of pancreatic enzymes, bile, and intestinal secretions.

Peristalsis and the normal loss of intestinal epithelial cells remove microorganisms. If peristalsis is slowed (eg, because of drugs such as belladonna or opium alkaloids), this removal is delayed and prolongs some infections, such as symptomatic shigellosis and Clostridioides difficile–induced colitis.

Compromised gastrointestinal defense mechanisms may predispose patients to particular infections (eg, achlorhydria predisposes to Salmonella, Campylobacter, and C. difficile infections).

Normal bowel flora can inhibit pathogens alteration of this flora with antibiotics can allow overgrowth of inherently pathogenic microorganisms (eg, Salmonella Typhimurium), overgrowth and toxin formation of C. difficile, or superinfection with ordinarily commensal organisms (eg, Candida albicans).

Genitourinary tract

Genitourinary tract barriers include the length of the urethra (20 cm) in men, the acid pH of the vagina in women, the hypertonic state of the kidney medulla, and the urine urea concentration.

The kidneys also produce and excrete large amounts of Tamm-Horsfall mucoprotein, which binds certain bacteria, facilitating their harmless removal.


Basic biology of bats

Across mammalian orders, Chiroptera (bats) is a species-rich taxon that stands out as it is uniquely capable of powered flight bats represent 1,423 of the more than 6,400 known species of mammal 10,11 (Table 1). This diversity is matched by their wide geographical distribution, which spares only the polar regions, extreme desert climates and a few oceanic islands 12 . Bats are keystone species upon which other fauna and flora are highly dependent for fertilization, pollination, seed dispersal and control of insect populations 13,14 . Bats roost in foliage, rock crevices and caves, and hollowed trees, as well as human-made structures such as barns, houses and bridges 15 . Different species may be homo- or heterothermic, using hibernation or shorter, daily episodic torpor to conserve energy 16 . Bats are prone to low fecundity and use reproductive strategies such as the storage of sperm or prolonged pregnancies, with either seasonal or aseasonal reproductive cycles 15 . Furthermore, they consume a wide range of diets—including nectar, fruit, pollen, insects, fish and blood (as in the common vampire bat (Desmodus rotundus)). Ever intriguing to humankind, bats possess the sensing powers of echolocation and magnetoreception (the ability to differentiate polar south from north), both of which are used primarily by microbats 17,18,19 . Differences in ecology, biology and physiology are important factors that must be considered in species-specific responses within bats and in the conduction of experimental studies.

Despite the advantages and efficiency of aerial transport, flight is a metabolically costly mode of locomotion 20 : the metabolic rates of bats in flight can reach up to 2.5–3× those of similar-sized exercising terrestrial mammals 21 . This enormous energy demand results in the depletion of up to 50% of their stored energy in a day—nectarivorous bats catabolize their high-energy diet of simple sugars as rapidly as 8 min after consumption, and flying bats consume about 1,200 calories of energy per hour 22,23,24 . Bats possess several metabolic adaptations and optimized airflow patterns to circumvent high-energy expenditures that could otherwise lead to starvation and death 25 . A key adaptation is the marked alteration of heart rate, which increases by 4–5× during flight to a maximum of 1,066 beats per minute 24 . To compensate for high levels of cardiac stress, cyclic bradycardia is induced for 5–7 min several times per hour during rest, which may conserve up to 10% of available energy. Despite their high metabolic rates and small statures, bats live substantially longer than non-flying mammals of similar body mass 26,27 . When adjusted for body size, only 19 species of mammals are longer-lived than humans: 18 of these species are bats (the other is the naked mole-rat) 28 . On average, the maximum recorded lifespan of bats is 3.5× that of a non-flying placental mammal of a similar size 29 . As a mammalian model of antiageing, bats may offer vital clues in human attempts to delay mortality and enhance longevity.


Mucosal Immune Memory

A subset of T and B cells of the mucosal immune system differentiates into memory cells just as in the systemic immune system. Upon reinvasion of the same pathogen type, a pronounced immune response occurs at the mucosal site where the original pathogen deposited, but a collective defense is also organized within interconnected or adjacent mucosal tissue. For instance, the immune memory of an infection in the oral cavity would also elicit a response in the pharynx if the oral cavity was exposed to the same pathogen.

Vaccinologist

Vaccination (or immunization) involves the delivery, usually by injection as shown in Figure 3, of noninfectious antigen(s) derived from known pathogens. Other components, called adjuvants, are delivered in parallel to help stimulate the immune response. Immunological memory is the reason vaccines work. Ideally, the effect of vaccination is to elicit immunological memory, and thus resistance to specific pathogens without the individual having to experience an infection.

Figure 3. Vaccines are often delivered by injection into the arm. (credit: U.S. Navy Photographer’s Mate Airman Apprentice Christopher D. Blachly)

Vaccinologists are involved in the process of vaccine development from the initial idea to the availability of the completed vaccine. This process can take decades, can cost millions of dollars, and can involve many obstacles along the way. For instance, injected vaccines stimulate the systemic immune system, eliciting humoral and cell-mediated immunity, but have little effect on the mucosal response, which presents a challenge because many pathogens are deposited and replicate in mucosal compartments, and the injection does not provide the most efficient immune memory for these disease agents. For this reason, vaccinologists are actively involved in developing new vaccines that are applied via intranasal, aerosol, oral, or transcutaneous (absorbed through the skin) delivery methods. Importantly, mucosal-administered vaccines elicit both mucosal and systemic immunity and produce the same level of disease resistance as injected vaccines. Currently, a version of intranasal influenza vaccine is available, and the polio and typhoid vaccines can be administered orally, as shown in Figure 4.

Figure 4. The polio vaccine can be administered orally. (credit: modification of work by UNICEF Sverige)

Similarly, the measles and rubella vaccines are being adapted to aerosol delivery using inhalation devices. Eventually, transgenic plants may be engineered to produce vaccine antigens that can be eaten to confer disease resistance. Other vaccines may be adapted to rectal or vaginal application to elicit immune responses in rectal, genitourinary, or reproductive mucosa. Finally, vaccine antigens may be adapted to transdermal application in which the skin is lightly scraped and microneedles are used to pierce the outermost layer. In addition to mobilizing the mucosal immune response, this new generation of vaccines may end the anxiety associated with injections and, in turn, improve patient participation.


ELF4 facilitates innate host defenses against Plasmodium by activating transcription of Pf4 and Ppbp

Platelet factor 4 (PF4) is an anti-Plasmodium component of platelets. It is expressed in megakaryocytes and released from platelets following infection with Plasmodium Innate immunity is crucial for the host anti-Plasmodium response, in which type I interferon plays an important role. Whether there is cross-talk between innate immune signaling and the production of anti-Plasmodium defense peptides is unknown. Here we demonstrate that E74, like ETS transcription factor 4 (ELF4), a type I interferon activator, can help protect the host from Plasmodium yoelii infection. Mechanically, ELF4 binds to the promoter of genes of two C-X-C chemokines, Pf4 and pro-platelet basic protein (Ppbp), initiating the transcription of these two genes, thereby enhancing PF4-mediated killing of parasites from infected erythrocytes. Elf4 -/- mice are much more susceptible to Plasmodium infection than WT littermates. The expression level of Pf4 and Ppbp in megakaryocytes from Elf4 -/- mice is much lower than in those from control animals, resulting in increased parasitemia. In conclusion, our study uncovered a distinct role of ELF4, an innate immune molecule, in host defense against malaria.

Keywords: ELF4 PF4 PPBP Plasmodium innate immunity malaria mouse transcription regulation.

Conflict of interest statement

The authors declare that they have no conflicts of interest with the contents of this article


Uncovering How Viruses Evade Cell Defenses

James Hurley is known to his peers as a structural biologist. But it was in physics, not biology, that he got his start in science. After earning his bachelor&rsquos degree in physics, Hurley entered a biophysics Ph.D. program to study molecular structures. Now, he researches interactions between cellular membranes and proteins&mdashincluding those created by viruses&mdashas a structural biologist at the University of California, Berkeley. He cites many factors for inspiring his decision to pursue biology and biophysics, including a desire to work on topics more closely tied to society and everyday life, such as AIDS&mdashthe 1980s AIDS epidemic took hold in the US when Hurley was beginning his research career. Hurley spoke with Physics about his work and about what physicists can bring to biology research.

All interviews are edited for brevity and clarity.

What is the focus of your research?

I&rsquom particularly fascinated by cellular structures that need to change shape rapidly over time. The most far-out example of this phenomenon is probably autophagy, which is when a cell swallows up and destroys some waste product or foreign matter. During this process, a double-membrane vesicle&mdashwhich starts out looking like a cup and then grows into a roughly spherical shape&mdashforms de novo in the cell in a matter of minutes. And this vesicle can engulf and eat other things in the cell, including invading pathogens.

Interactions between cell membranes and pathogens become even more interesting when you consider that intercellular pathogens also manipulate cell membranes&mdashfor example, to cross the membrane. Their mechanisms can be elaborate and can eliminate a cell&rsquos defenses rather than just slip through them.

What have you learned about pathogens and cellular defenses?

In apes and monkeys, there is an endemic ancestor of the HIV virus called SIV. It&rsquos been around for hundreds of thousands of years, but it only passed to humans as HIV about 100 years ago. My collaborators and I determined the molecular structures that explain how humans had been able to avoid the virus, and therefore AIDS, for so long.

Humans share more than 99% of our DNA with chimpanzees, but there are a few significant differences. One of them is in a protein called tetherin, which affects our susceptibility to viruses. Tetherin is a defense molecule that restricts the ability of viruses to replicate. In apes and monkeys, SIV targets a specific piece of this defense molecule, holding onto it like a handle and then destroying the molecule. But in humans, that piece of tetherin is missing we have somehow removed the handle that SIV uses to undermine ape and monkey defenses.

My group didn&rsquot discover the &ldquohandle&rdquo mechanism. But we came up with a picture of the handle that really highlights the molecular differences in ape and monkey versus human tetherin.

You are also working on the virus that causes COVID-19. Can you share what your group is investigating?

Coronaviruses in general, not just SARS-CoV-2, which causes COVID-19, replicate in membrane-delimited compartments within host cells. So we&rsquore very interested in how coronavirus proteins work to reshape host-cell membranes. And, like HIV, coronaviruses have ways of undermining host defenses&mdashSARS-CoV-2, for example, also grabs onto handles in our defense proteins and disarms them.

There are thousands of other coronaviruses in bats and other animals that have not crossed over to humans. Others have induced only mild colds, and more serious ones, such as SARS and MERS, were quickly contained. What&rsquos the difference between them and the pandemic-causing SARS-CoV-2? One thing, we think, is that SARS-CoV-2 has developed quicker, more potent ways to undermine our host defenses. So we are looking at that to see if this coronavirus has any unique invasion mechanisms that are absent in others.

Finding such a mechanism won&rsquot necessarily lead to a treatment, but I think it would be helpful for understanding how this disease came to be so bad.

Where does physics show up in your work?

It&rsquos everywhere. It&rsquos in the forces that dictate biomolecular interactions. It&rsquos in the probes that we use to determine molecular structures&mdashprimarily, electron microscopy and x-ray diffraction. And it&rsquos in the shapes of membranes. For example, at low resolution, we use elasticity theory to calculate how much energy it takes to bend the membrane into a particular shape. To study these phenomena at higher resolution, we use molecular simulations, which are also based on these forces of physics.

Do you have any advice for physics students interested in a career in biophysics or biology research?

An undergraduate degree in physics is a fantastic springboard into a biology or biophysics Ph.D. It often helps if the student has completed a couple of biological courses or volunteered in a biologically oriented lab, but that isn&rsquot essential. Transitioning at the postdoc level is also possible. One of my star postdocs had a Ph.D. in physics and had never touched any sort of biological equipment before joining my lab.

There are many opportunities for people who have strong computational and math skills and who are interested in understanding how life is organized or in curing diseases. Jump on over, the water&rsquos warm.

Erika K. Carlson is a Corresponding Editor for Physics based in New York City.


How high frequency of HLA-B*51 explains the high frequency of the I135X mutation in Japanese with other HLAs. Introduction: Human immunodeficiency virus (HIV) is the group of retrovirus that is sexually transmitted from one to another. It causes a disease that leads to life-threatening infections called AIDS. Here, immune system fails or weakens due to the viral infection and is accompanied with the development of many infections. Certain proteins called human leukocyte antigen (HLA) are produced and displayed by our cells that act as marker for identification of unusual invaders in the body. Each unique marker is produced for the determination of self cells versus the invaders by the immune system.

To determine: How high frequency of HLA-B⩑ explains the high frequency of the I135X mutation in Japanese with other HLAs.

Introduction: Human immunodeficiency virus (HIV) is the group of retrovirus that is sexually transmitted from one to another. It causes a disease that leads to life-threatening infections called AIDS. Here, immune system fails or weakens due to the viral infection and is accompanied with the development of many infections. Certain proteins called human leukocyte antigen (HLA) are produced and displayed by our cells that act as marker for identification of unusual invaders in the body. Each unique marker is produced for the determination of self cells versus the invaders by the immune system.


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Hijacking the Host Defenses Gives Bacteria an Advantage (Biology)

Bacteria that cause life-threatening infections sometimes resort to the nastiest ploy of all: Stealing the human body’s defense weapons and exploiting them to their own advantage. Researchers at the Weizmann Institute of Science have now uncovered one such strategy used by Salmonella.

When Salmonella bacteria penetrate the human gut, they can cause diarrhea and other symptoms of food poisoning that often stay mild, but if they get into the bloodstream and from there into the liver, spleen and other body organs, they are liable to cause more severe disease that can be fatal. In the case of such invasion, large protective cells called macrophages try to stop the infection by swallowing the Salmonella whole. The bacteria, however, sometimes manage not only to survive but to thrive inside the macrophages, even converting them into incubators that facilitate their spread.

In a study led by doctoral student Gili Rosenberg in the lab of Dr. Roi Avraham of Biological Regulation Department, the researchers started out by exposing macrophages to Salmonella and examining the changes that occur in these cells. As the macrophages gear up to fight the bacteria, their metabolism undergoes such a major shift that they switch from producing energy in the cellular organelles called mitochondria to a massive burning of glucose. But when the scientists blocked this metabolic shift in the macrophages, they found – to their surprise – that the bacteria, instead of growing more aggressive, became less virulent.

This finding suggested that the virulence of Salmonella was somehow dependent on the metabolic shift. In other words, the very changes in cellular metabolism that were intended to help the macrophages deal with the infection could be hijacked and abused by Salmonella. The scientists checked all the metabolites that accumulate in macrophages when they fight Salmonella, and they zeroed in on a compound called succinate. This compound is known to act as a signaling molecule that the macrophages use to activate their defenses against invading bacteria: Succinate promotes the recruitment of the immune system and the generation of toxic inflammatory compounds that can kill the bacteria.

(l-r) Gili Rosenberg and Dr. Roi Avraham © WIS

But as the scientists discovered, the bacteria – in the course of evolution – had learned to make use of this very molecule as a signal to become more virulent and to manipulate the contents of the macrophages to their own benefit. Succinate, as they found, activates certain bacterial genes, causing the Salmonella to grow a needle that punctures vacuoles –closed compartments within the macrophage that keep bacteria wrapped in “hazmat” padding. The needle then secretes substances that neutralize the giant cell’s killing mechanism. On top of this, succinate activates a mechanism that protects the Salmonella from antimicrobial peptides secreted within macrophages, so that the bacteria now feel free to treat the macrophage as a hotel, with all the amenities.

To confirm that these manipulations are indeed dependent on succinate, the scientists genetically engineered Salmonella to disable the transporter molecule that enables these bacteria to take up succinate, and compared the mutant bacteria to unaltered ones – that is, ones that can make full use of succinate. The mutant bacteria failed to survive inside macrophages and were much less effective at infecting mice than the unaltered ones.

The bacteria – in the course of evolution – had learned to make use of this very molecule as a signal to become more virulent

In addition to providing insights into infection by Salmonella, the study’s results pave the way to investigating whether other intracellular bacteria hijack the immune metabolites that accumulate in macrophages following bacterial infection. These might include the bacteria responsible for tuberculosis, as well as Listeria, which can cause a form of meningitis and other severe infections, and Shigella, a common cause of children’s diarrhea in Africa and South Asia.

The study’s findings may serve as a basis for developing antibacterial therapies to block the uptake of succinate by bacteria such drugs would be more targeted than existing antibiotics.

Salmonella (bright green) inside macrophages (brownish yellow), viewed under a microscope © WIS

“Whereas antibiotics kill all bacteria, including the good ones, a therapy based on blocking succinate can be aimed at killing only those that cause disease,” Rosenberg says.

Study participants included Dror Yehezkel, Dotan Hoffman, Leia Vainman, Noa Nissani, Dr. Shelly Hen-Avivi, Dr. Shirley Brenner, Dr. Noa Bossel Ben-Moshe and Hadar Ben-Arosh of the Biological Regulation Department and Dr. Maxim Itkin and Dr. Sergey Malitsky of the Life Sciences Core Facilities Department.

Dr. Roi Avraham’s research is supported by the Sagol Weizmann-MIT Bridge Program the Pasteur-Weizmann Delegation the estate of Zvia Zeroni and the European Research Council. Dr. Avraham is the incumbent of the Philip Harris and Gerald Ronson Career Development Chair.

Featured image: Macrophages, large immune cells, “swallow” bacteria whole. Getty images


Microbial Arsenal of Antiviral Defenses - Part I

Bacteriophages or phages are viruses that infect bacterial cells (for the scope of this review we will also consider viruses that infect Archaea). Constant threat of phage infection is a major force that shapes evolution of the microbial genomes. To withstand infection, bacteria had evolved numerous strategies to avoid recognition by phages or to directly interfere with phage propagation inside the cell. Classical molecular biology and genetic engineering have been deeply intertwined with the study of phages and host defenses. Nowadays, owing to the rise of phage therapy, broad application of CRISPR-Cas technologies, and development of bioinformatics approaches that facilitate discovery of new systems, phage biology experiences a revival. This review describes variety of strategies employed by microbes to counter phage infection, with a focus on novel systems discovered in recent years. First chapter covers defense associated with cell surface, role of small molecules, and innate immunity systems relying on DNA modification.

Keywords: BREX CRISPR-Cas DISARM Dnd systems antiviral defense bacteriophages immunity systems phage–host interactions phosphorothioate restriction–modification.


Watch the video: Host defense mechanism. microbial pathogenies (September 2022).


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