1、Lecture 8BIOL 5331Microbial Interference with Host DefensesBIOL 533Lecture 8Medical MicrobiologyLecture 8BIOL 5332Overall Strategies Defense against complement Subversion of phagocytosis Subversion of immune responsesLecture 8BIOL 5333General Aspects Pathogen finds itself in hostile territory Host f
2、ights back and usuallybut not alwayswins Hosts defenses are interrelated and so are organisms countermeasuresLecture 8BIOL 5334General Aspects Given organism sometimes has numerous different virulence factors Does not have to harm tissue to be called virulence factor,although many do Have to determi
3、ne precise role of each factor if a large number are involved Not always sure in vitro situation is same as in disease stateLecture 8BIOL 5335Defense Against Complement Overall strategies Inhibit complement activation Mask activating substances Capsule IgA antibodies Cover up target of complement me
4、mbrane attack complexLecture 8BIOL 5336Defense Against Complement Overall strategies,continued Appropriate inhibitor to activation to surface Inactivate complement chemotaxin C5aLecture 8BIOL 5337Prevent Complement Activation Masking surface components that activate by the alternative pathway Capsul
5、es Murein of S.aureus good activator,but is covered by capsule Capsules rich in sialic acid of Group B streptococci and strains of E.coliLecture 8BIOL 5338Prevent Complement Activation IgA antibodies Meningococci get coated with IgA antibody Does not activate complement Prevents other Ab that can ac
6、tivate from reaching surface of cellLecture 8BIOL 5339Prevent Complement Activation Cost of having capsule antigenic Elicits activation by primary pathway Defend better against immediate defenses than later onesLecture 8BIOL 53310Prevent Complement Activation Cover up target of membrane attack compl
7、ex(outer membrane)Gram,such as Salmonella or E.coli Smooth strains with long 0 antigen polysaccharide chain do not allow access of mac while rough strains(with little or no 0 antigen)do Correlates with pathogenicityLecture 8BIOL 53311Subversion of Phagocytosis Overall strategies Inhibition of phagoc
8、yte recruitment Microbial killing of phagocytes Escape of ingestionLecture 8BIOL 53312Subversion of Phagocytosis Overall strategies,continued Survival inside phagocytes Escape into the cytoplasm Inhibition of lysosome and phagosome fusion Resistance to lysosomal enzymes Inhibition of phagocyte oxida
9、tive pathway Antibody effects(host counters)Lecture 8BIOL 53313Subversion of Phagocytosis General aspects Being inside cell is not necessarily bad for an organism Powerful strategy is to grow within nonphagocytic cell Shielded from antibodies and drugsLecture 8BIOL 53314Subversion of Phagocytosis In
10、hibition of phagocyte recruitment Direct inhibition of neutrophil motility and chemotaxisBordetella pertussis produces toxins Adenylate cyclase toxin Increase cyclic AMP in neutrophils Leads to paralysis Pertussis toxin Impairs migration of monocytesLecture 8BIOL 53315Subversion of Phagocytosis Micr
11、obial killing of phagocytes Leukocidins(exotoxins)kill neutrophils and macrophages Can work at distance or after ingestion Typical producers are highly invasive bacteriaPseudomonas,staphylococci,group A streptococci,gas gangrene clostridiaLecture 8BIOL 53316Subversion of Phagocytosis Escaping ingest
12、ion Naked capsule is effective(pneumococci)Opsonized bacteria not as effective Countering opsonization by complement components or Ab Any mechanism inhibits Activation of complement Synthesis or activity of AbLecture 8BIOL 53317Subversion of Phagocytosis Escaping ingestion,continued Countering opson
13、ization when antibodies are present Staphylococci and streptococci Make surface component(protein A)Binds to IgG molecules by the wrong end(Fc region)Cannot act as opsonins because Fc region not free to bind to Fc receptors on phagocytic cells Not known if antiphagocytic defense is relevant to disea
14、se processLecture 8BIOL 53318Subversion of Phagocytosis Survival inside phagocytes Escape into cytoplasm Rickettsia(Rocky Mountain Spotted Fever)or trypanosomes of Chagas disease cross membrane of phagosome to enter cytoplasm Since lysosomes do not secrete contents into cytoplasm,organism is safe Ho
15、w they enter cytoplasm is not known for certain Possess surface-bound phospholipase,which may weaken membraneLecture 8BIOL 53319Subversion of Phagocytosis Survival inside phagocytes,continued Inhibition of lysosome and phagosome fusion Examplesbacteria that cause:Tuberculosis Psittacosis Legionnaire
16、s diseaseLecture 8BIOL 53320Subversion of Phagocytosis Mechanism of tuberculosis Induced by complex glycolipids(sulfatides)not certain Facts:Inhibition must be due to modification of phagosome membrane Microorganism might contribute by compounds secreted or present on the surfaceLecture 8BIOL 53321S
17、ubversion of Phagocytosis Survival inside phagocytes,continued Resistance to lysosomal enzymessurvive in phagolysosome(pH as low as 4)Leishmania(protozoa)resistance may be due to:Resistant cell surfaces Excretion of enzyme inhibitorsLecture 8BIOL 53322Subversion of Phagocytosis Survival inside phago
18、cytes,continued Inhibition of phagocytes oxidative pathway Bacillus of Legionnaires disease Inhibits hexose-monophosphate shunt and oxygen consumption in neutrophils Reduces respiratory burst for killing microbes Staphylococciproduces catalase that degrades hydrogen peroxide necessary for oxidative
19、killingLecture 8BIOL 53323Subversion of Phagocytosis Survival inside phagocytes,continued Antibody effects:host counters parasite Sometimes help host guard against microbial survival measures Antibodies do not prevent entry into cells,but inhibit subsequent effects Rickettsia coated with antibody ca
20、nnot pass through membrane into cytoplasm Antibodies against Legionnella prevent inhibition of phagolysosomal fusionLecture 8BIOL 53324Subversion of Immune Response Immunosuppression:general aspects Host becomes susceptible to other infections and survival probability is lessenedLecture 8BIOL 53325S
21、ubversion of Immune Response AIDSinfects T4 inducer-helper lymphocytes Depletion of cells leads to collapse of immune system Reduction in circulating lymphocytes Impaired delayed hypersensitivity Defective responses of T cells to Ag Reduction in T-cell numbers cytotoxic for tumor cells and virus inf
22、ected cellsLecture 8BIOL 53326Subversion of Immune Response B cell function is also impaired Reduced production of specific Ig Increased chaotic production of nonspecific IgLecture 8BIOL 53327Subversion of Immune Response Other immunosuppressive viruses:Measles Tuberculosis more common after widespr
23、ead measles outbreaks Infected T cells in vitro do not die Lose certain functions,including ability to mount delayed hypersensitivity responseLecture 8BIOL 53328Subversion of Immune Response Infected B cells in vitro Stop synthesizing and releasing Ig Primary effect on B cells Not secondary to actio
24、n of virus on T cells or macrophageLecture 8BIOL 53329Subversion of Immune Response Other immunosuppressive viruses:Hepatitis B and influenza Impair function of lymphoid cells without causing major structural damage Immune suppression as a result of inhibition of synthesis of lymphokines Leishmanias
25、(protozoa)Lecture 8BIOL 53330Subversion of Immune Response Leishmanias(protozoa)when grown in macrophage Suppress secretion of interleukin-1 Important for initiating series of inflammatory and immunological reactions important for the eradication of the organism Also explains T cell unresponsiveness
26、 Suppresses capacity of macrophage to make class I and class II products of major histocompatibility locus(MHC)Potential for marked suppression of cell-mediated immunityLecture 8BIOL 53331Subversion of Immune Response Final thoughts Infection of lymphocytes is not immuno-suppressive in nature Large
27、number of organisms infect lymphoreticular tissues,but do not cause global disturbances to host immunity Bacteria that cause typhoid fever or brucellosis live in lymph nodes for long period of time Do not induce noticeable immune suppressionLecture 8BIOL 53332Subversion of Immune Response Frequent c
28、hanging of antigenic coats(antigenic variation)Examples of bacteria,viruses,and protozoa Trypanosomes(protozoa)GonococciBorrelia(recurrent fever)Influenza virusesLecture 8BIOL 53333Subversion of Immune ResponseTrypanosoma brucei(causative agent of sleeping sickness)Infects blood of interstitial flui
29、ds of animals and man Exposed to circulating AbLecture 8BIOL 53334Subversion of Immune ResponseTrypanosoma brucei,continued Covered with thick protein coat(variable surface glycoprotein)Undergoes antigenic shifts during infection Have several hundred genes that encode different antigens,but express
30、only one at a timeLecture 8BIOL 53335Subversion of Immune ResponseTrypanosoma brucei,continued When antibodies against one type are made:Number of parasites in blood drops Soon replaced by new antigenic type Can be many successive waves of antigenic changes in a single host Protective immunity does
31、not function wellLecture 8BIOL 53336Subversion of Immune Response Gonococcus and its adhesin Periodic change in Pilin(protein fimbriae;attach to cells)Major outer membrane proteinsLecture 8BIOL 53337Subversion of Immune Response Antigenic variation among influenza virusesmajor obstacle to effective
32、vaccine(year after year)Definitions Antigenic driftminor changes that occur every 2 to 3 years Antigenic shiftmajor changes that occur about every 10 yearsLecture 8BIOL 53338Subversion of Immune Response Antigenic variation,continued Mechanism involves two proteins Hemagglutinin-binds to cell recept
33、ors Neuraminidase-changes receptorsLecture 8BIOL 53339Subversion of Immune Response Proteolysis of antibodies Make extracellular proteases that inactivate secretory IgA antibody(major Ab type on human mucosal surfaces;subclasses I and II)Cleave only subclass I at hinge region to leave complete by in
34、active peptide fragments Examples:Gonococci,meningococci,Haemophilus influenzae,and some pathogenic dental streptococciLecture 8BIOL 53340Subversion of Immune Response Proteolysis of antibodies,continued Specificity of IgA1 proteases from different bacteria Highly specific for subclass I Biochemical
35、 and genetic differences that suggest property evolved independently Presence in fluids and tissues Active form in infected tissues and fluidsLecture 8BIOL 53341Subversion of Immune Response Proteolysis of antibodies,continued Possible relationship to pathogenicity;suggested,not proven Nonpathogeic
36、relatives lack these proteases Fabulation(cleavage with Fab fragment attached)Ag unavailable for binding with intact antibody molecules May serve to protect some organisms against AbLecture 8BIOL 53342Subversion of Immune Response Other viral survival strategies:general aspects Chronic infectionevad
37、e host defenses longerLecture 8BIOL 53343Subversion of Immune Response Herpes infection Do not usually enter extracellular fluid,but pass among cells through cytoplasmic bridges Can also be latent(reside within nerve cells but do not multiply)In these circumstances,not affect by antibodies,cell-mediated immunity,or interferon Survive for long periods of time,then later reactivate(perhaps when defenses are lower)Lecture 8BIOL 53344Lecture 8 Questions?Comments?Assignments.
