Pathology Mod 5: Host-Pathogen Interaction PDF

PATHOLOGY 09/04/2024. MOD 5: HOST-PATHOGEN INTERACTION Dr. Kevin A....

PATHOLOGY 09/04/2024. MOD 5: HOST-PATHOGEN INTERACTION Dr. Kevin A. Elomina TWG: 5A | FE: AU | FCE: AR TAKE HOME POINTS MRSA expresses a different form The outcome of an infection depends on the balance of penicillin-binding protein called between the pathogen’s virulence and the nature and PBP2A, which has lower affinity magnitude of the host response. to penicillin, making it less Pathogens can either alter themselves or their effective environment in order to escape the host immune system and cause infection. Carbohydrate capsule prevents The response to infection is inflammation that can take phagocytosis (e.g., many patterns depending on the type of pathogen and Streptococcus pneumoniae) host immune response. Resistance to S. aureus: Protein A binds Fc There are different mechanisms by which organisms can killing by receptors of antibodies, cause disease. phagocytosis decreasing antibody binding to There are special types of infections with unique Fc receptors of phagocytes implications to management. M. tuberculosis: inhibits phagolysosomal fusion I. IMMUNE EVASION BY MICROBES Viruses can limit viral gene One of the two functions of our immune system is to expression causing latency, with protect us from foreign invaders. Establishment of full gene expression and Infections occur if these foreign invaders are: latent infection: replication occurring after ○ Smart enough to evade the watchful eyes of our Ïnvisibility reactivation immune system; or Examples: HSV and ○ Strong enough to withstand the onslaught by Varicella-Zoster virus our immune system TWO GENERAL MECHANISMS OF IMMUNE EVASION B. “DEBUFF” STRATEGIES BY MICROBES Common theme: the change should be directed to the ENEMY (immune system) BUFF DEBUFF Usually found in virus infected cells. Once a virus enters a cell, it hijacks its metabolism to Applying a skill to “Applying a skill to your favor production of viral particles and to ensure that the YOURSELF to boost your ENEMIES to weaken their immune system will tolerate the virus infected cell. abilities” abilities” Pathogen changes itself to: Pathogen changes HOW DEBUFFING STRATEGIES Escape (or avoid) the immune system reacts Production of Production of proteins that recognition to it, in favor of its survival, anti-apoptotic inhibit apoptosis, induce Withstand (or survive) to tolerate it (e.g. dampen proteins (or latency, or transform infected the attack by the normal immune response). evasion of cells (uncontrolled cell growth) immune system and apoptosis and Usually seen in virus-infected other threats (e.g. manipulation of cells antimicrobial host cell substances) metabolism) A. “BUFF” STRATEGIES Production of "decoy" factors Common theme: the change should be directed to that inhibit interferon action one’s self and NOT the immune system. Resistance to Usually seen in virus-infected cytokine-, cells chemokine-, and Orthopoxviruses: produce Buffing Strategies complement- soluble proteins that bind mediated host interferon, preventing its Antigenic drift and shift in Influenza defense interaction with interferon viruses receptors, causing decreased Influenza virus can undergo Antigenic interferon response genetic reassortment giving Variation: rise to a set of different surface Impaired antigen presentation “Transformation” antigens (antigenic drift) or an Evasion of to T cells by disrupting major overall different variant recognition by histocompatibility complex (antigenic shift) CD4+ helper T (MHC) proteins, causing cells and CD8+ impaired immune response Resistance to Methicillin-resistant Staphylococcus cytotoxic T cells Usually seen in virus-infected antimicrobial aureus (MRSA) cells (Herpes Simplex Virus, peptides Pathology - Mod 5 Host-Pathogen Interaction 1 of 8 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  Cytomegalovirus, Neutrophils are also capable of damaging host tissues Epstein-Barr Virus) (tissue destruction), hence the accompanying background necrotic debris. Programmed death-1 (PD-1) receptor activation via its ligand (PD-L1) causes T-cells to tolerate virus-infected cells Downregulation leading to poor T cell response of anti-microbial (T cell exhaustion) T cell response Examples: HIV and Hepatitis C virus Tumors also employ this strategy to avoid host immune attack II. HOST’S INFLAMMATORY RESPONSE TO INFECTION Infectious agents trigger inflammation which can take SIX (6) patterns depending on the pathogen and immune status of the patient. In every type of response, you must identify the following: ○ Gross (if applicable) and microscopic findings of each type ○ Pathophysiology of each pattern (HOW such Acute Mastitis (numerous neutrophils on a background of responses occur) pink-purple necrotic debris). ○ Common organisms associated with each pattern B. MONONUCLEAR Instead of neutrophils or polymorphonuclear cells, Patterns of Inflammation mononuclear cells such as lymphocytes, plasma cells, and macrophages are seen. 1 Suppurative (Purulent) NEUTROPHILS have short half-lives and after the 3rd day of injury, macrophages appear at the site of 2 Mononuclear infection. MACROPHAGES have longer half-lives, can 3 Granulomatous phagocytize pathogens and present their antigens to T cells in order to produce chronic inflammation. 4 Cytopathic and cytoproliferative This type of response is also seen in acute viral 5 Tissue Necrosis infections because lymphocytes respond to intracellular pathogens. 6 Chronic Inflammation and Scarring MONONUCLEAR INFLAMMATION 0 No Reaction (no inflammatory response at all) MICROSCOPI Mononuclear cells such as A. SUPPURATIVE (PURULENT) C lymphocytes, plasma cells, and macrophages SUPPURATIVE INFLAMMATION PATHO- Long-standing infections involve PHYSIOLOG chronic inflammation GROSS Pus (on physical examination), Y (mononuclear cells) (indications or abscess, purulent material Acute viral infections key words) (lymphocytes respond to intracellular pathogens) MICROSCOP Neutrophils, necrotic debris IC (Neutrophilic infiltration, liquefactive ORGANISMS Viruses necrosis) (cause) Long-standing infections PATHO- Pyogenic bacteria trigger intense acute EXAMPLES Plasma cell-rich inflammation in PHYSIOLOG inflammation and tissue damage primary and secondary syphilis Y lesions Lymphocytic inflammation in viral ORGANISMS Caused by pyogenic or pus-forming infections of the brain and bacteria, most common are: meninges (meningoencephalitis) Staphylococcus aureus Streptococcus pyogenes C. GRANULOMATOUS Called “PYOGENIC” because these can trigger an A special pattern of chronic inflammation characterized intense, acute inflammatory response. by the presence of granulomas Therefore, this type characteristically has a lot of Granulomas form from macrophages when infectious neutrophils. agents trigger the Th1 response which is under the domain of CD4+ T cells. Pathology - Mod 5 Host-Pathogen Interaction 2 of 8 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  ○ Therefore, an intact cell-mediated immunity is required for granulomas to form. Multinucleation: multinucleated giant cells (polykaryons) Cytoproliferative: infection causes GRANULOMATOUS INFLAMMATION increased proliferation of host cells (a key property of oncogenic or tumorigenic MICROSCOPIC Granuloma (caseating or viruses) non-caseating) Cellular proliferation Tumor formation PATHO- Organisms trigger the Th1 response PHYSIOLOGY to form granulomas (intact PATHO- Cytopathic: accumulation of viral (common cell-mediated immunity is required) PHYSIOLOG proteins and virus-mediated cell-cell theme) Y fusion Cytoproliferative: expression of ORGANISMS “Hardy” (hard to eliminate) oncogenic viral products (cause) organisms Mycobacteria — e.g., M. ORGANISMS Viruses tuberculosis (most classic) Fungi (e.g. Histoplasma EXAMPLES Cytopathic: capsulatum) Herpes Simplex Virus (HSV) Schistosome eggs Cytomegalovirus (CMV) Cytoproliferative: Epstein-Barr Virus (EBV): causes proliferation of atypical lymphocytes and can cause Nasopharyngeal carcinoma and Burkitt lymphoma Human Papillomavirus (HPV): high-risk HPV (Types 16 and 18) can cause squamous cell carcinomas in the oropharynx and anogenital region Remember: When there are inclusions and multinucleations in host cells, most likely the etiologic agent is a virus. Pulmonary Tuberculosis [granuloma with central caseation necrosis and scattered Langhans type giant cells (arrow)]. D. CYTOPATHIC AND CYTOPROLIFERATIVE The words cytopathic and cytoproliferative are associated with viruses. 1. CYTOPATHIC When a virus enters a cell, it hijacks the cellular machinery of the cell in favor of virus production ○ Viral proteins can accumulate and form inclusions and virus-mediated cell-to-cell fusion can produce multinucleated giant cells. 2. CYTOPROLIFERATIVE Cytopathic — Herpes, cervical pap smear [pink-purple Oncogenic or tumorigenic viruses are viruses that intranuclear inclusions (small arrow) and multinucleated giant can cause tumor growth cells or polykaryons (large arrow). The inclusions are made ○ Incorporate their genome into host genome up of viral proteins]. ○ Use the host cellular machinery to transcribe and translate their genes ○ Their gene products promote unregulated cell proliferation and prevent cell death, causing tumor formation. CYTOPATHIC AND CYTOPROLIFERATIVE INFLAMMATION MICROSCOP Cytopathic: produces abnormal cellular IC morphology as a consequence of viral infection: Inclusions ○ Inclusion bodies: intranuclear Cytoproliferative — Atypical lymphocytes in infectious and/or intracytoplasmic mononucleosis [increased number of atypical lymphocytes with abundant cytoplasm, irregular nuclear contour, and Pathology - Mod 5 Host-Pathogen Interaction 3 of 8 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  visible nucleoli. This infection is caused by EBV. A photo of ○ Even granulomas heal by fibrosis as exemplified by normal lymphocytes (inset) is shown for reference]. 5-step fibrosis in the liver of patients with Schistosomiasis E. TISSUE NECROSIS Some infections lead to tissue necrosis with Characteristics of Chronic Inflammation and Scarring disproportionately low-density inflammation. ○ This is because the organism produces toxins that GROSS Increased fibrous tissue cause destruction of cellular components like the plasma membrane, a feature also seen in necrosis. MICROSCOPI Mononuclear inflammation and fibrosis The toxin action causes rapid and severe necrosis that C microscopically shows coagulative necrosis or gangrenous necrosis when it involves multiple tissue PATHO- Long-standing inflammation heals by planes. PHYSIOLOG connective tissue deposition Aside from tissue necrosis, gas bubbles may be Y observed because of bacterial fermentation. ORGANISMS Non-specific – as long as the infection (cause) is long-standing or chronic it can lead to Characteristics of Tissue Necrosis scarring Chronic inflammation eventually GROSS Reddish-black necrotic tissue causes tissue fibrosis (scarring) MICROSCOP Coagulative or gangrenous necrosis EXAMPLES Pipestem fibrosis in IC Schistosome infections: Granulomatous inflammation PATHO- Toxin-induced destruction of cellular around eggs will heal by fibrosis, PHYSIOLOG components leading to more rapid and causing portal hypertension Y severe necrosis Cirrhosis in chronic Hepatitis B infection ORGANISMS Toxin-producing organisms (cause) Classic example: Clostridium One of the golden rules of inflammation: when perfringens (clostridial something is chronically inflamed, fibrosis almost myonecrosis or gas gangrene) always comes after. ○ Produces α-toxin (lecithinase ○ The words “chronic” and “fibrosis” almost always go and sphingomyelinase) that together. degrades cell membranes and Fibrosis also means decrease in living tissue because it nerve sheaths, respectively, is replaced by fibrous scar tissue. causing clostridial myonecrosis ○ Clinically, this translates to decrease in or loss of (gas gangrene) organ function. Hepatic Cirrhosis [liver is divided into nodules of varying sizes (asterisks) by fibrous bands (arrow). If there is a history Clostridial myonecrosis [the skeletal muscle fibers are of chronic viral hepatitis (Hepatitis B or C) without any other eosinophilic with loss of nuclear details indicating coagulative risk factors, it may be the most likely cause]. necrosis, with gas bubbles (asterisk) because of bacterial fermentation. Gram stain (inset photo) shows Gram-positive G. NO REACTION rods (Clostridium perfringens)]. Happens when the immune system cannot respond to infections (no inflammatory response) F. CHRONIC INFLAMMATION AND SCARRING Organisms proliferate unimpeded WITHOUT Two (2) primary mechanisms of repair: significant inflammation or tissue reaction ○ Regeneration ○ Connective tissue deposition: main mechanism NO REACTION RESPONSE of repair in chronic inflammation Macrophages in long-standing infections produce factors that initiate healing by fibrosis: Pathology - Mod 5 Host-Pathogen Interaction 4 of 8 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  MICROSCOP Proliferation of organisms without Virus Entry Tropism: preferential infection of IC significant inflammation or tissue into the Host specific cells/tissues by viruses reaction Cell ○ Due to presence of compatible viral proteins and PATHO- Severe immune compromise causes host-cell surface receptors PHYSIOLOG inadequate immune response Examples: Y ○ HIV: HIV gp120 binds to CD4 and CXCR4 ORGANISMS Opportunistic pathogens: those that ○ EBV: binds to CD21 in B cells (usual cause infection only in Once inside, the virus can proceed associated immunocompromised individuals to the other three mechanisms organisms) (Mycobacteria, fungi) in the setting of stated below. profound immune compromise Direct Inclusion, multinucleation, and Cytopathic cell lysis Mycobacteria and fungi are also mentioned here, even Effect Viruses can cause cell damage and though they are already mentioned under granulomatous death by: conditions, because the type of host response against ○ Producing virus-related these pathogens depend on the immune status of the molecules at the expense of host. host cell molecules Granulomatous: for immunocompetent ○ Apoptosis by producing No reaction: for profoundly immunocompromised misfolded proteins or pro- apoptotic factors ○ Eventually lysing the cell as part of virus release Tissue Injury As the viral surface proteins are from Antiviral recognized by cytotoxic (CD8+) T Immune cells as foreign, virus infected cells Response are killed primarily by it. In the process, cytotoxic (CD8+) T cells can also cause tissue injury in the surrounding normal tissues Neoplastic Oncogenic (tumorigenic) viruses Transformatio incorporate their genes into the host’s n of Infected genome (integration of viral genome into Cells the host) causing: Expression of virus-encoded oncogenes (oncogenic viral products) causing uncontrolled cell Lepromatous leprosy [skin lesion does NOT show proliferation granulomas because of depressed cell-mediated immunity. Evasion of apoptosis Instead, numerous macrophages are seen. Fite-Farco stain Mutagenesis/Mutations for acid-fast bacilli shows balls of Mycobacterium leprae (globi) within macrophages (Lepra cells)]. B. MECHANISMS OF BACTERIAL INJURY III. MECHANISMS OF INJURY OF COMMON INFECTIOUS Virulence: the ability of the organism to infect and AGENTS cause damage to the host Pathogenicity: the ability of the organism to cause disease in a host A. MECHANISMS OF VIRAL INJURY Bacteria have virulence factors that may be: ○ Innately expressed in their chromosome; or ○ Acquired by assimilation of extrinsic genetic material. ○ E.g., plasmids, infection by a virulent bacteriophage Summary of how VIRUSES can cause injury to the HOST. MECHANISM DETAILS/EXAMPLES Summary of how BACTERIA can cause injury to HOST. Dr. Elomina’s lecture video Pathology - Mod 5 Host-Pathogen Interaction 5 of 8 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  MECHANIS DETAILS/EXAMPLES heart to also be attacked by the M immune system (molecular mimicry) Bacterial Some bacteria need to adhere to the host Adherence cells in order to establish infection and some Cell-mediated Immunity to Host have specialized structures for adhesion Cells such as pili or fimbriae Aggressins Bacterial enzymes that alter tissue Pili or fimbriae: surface structures for environment favoring growth or spread of adhesion an organism ○ E.g., P fimbriae (Pyelonephritis- Coagulase from S. aureus associated pili) of E. coli are used Streptokinase from S. pyogenes to attach to urothelial cells Collagenase and Hyaluronidase Adhesins: bacterial surface proteins that bind host cells or extracellular IV. SPECIAL TYPES OF INFECTIONS matrix Most common infections are community-acquired Bacterial Bacteria are also capable of producing (acquired outside of the hospital). Toxins toxins that can alter cellular There are special types of infections with unique and physiology or cause tissue damage. important clinical implications to management. Bacteria produce 2 broad kinds of toxins: A. HEALTHCARE-ASSOCIATED (NOSOCOMIAL) INFECTIONS Exotoxins Toxins that are released to the Infections acquired in the hospital (occupational or environment without cell lysis and they prolonged admission) are more serious because have various specific actions (more hospital bugs tend to demonstrate greater antibiotic specific effects). resistance. Enzymes or substances secreted by ○ Causing severe disease and delayed institution bacteria that have local or remote effects of effective antimicrobial therapy Cholera toxin: increases chloride ○ Such infections need more potent antibiotics for secretion into the intestinal lumen treatment causing profuse watery diarrhea Preventive measures involve strict infection control Toxic shock syndrome by S. aureus procedures including: and S. pyogenes ○ Engineering modification e.g., negative pressure ○ Superantigens: bind to many T rooms cells and cause massive T cell ○ Personal protective equipment (PPEs) proliferation and cytokine release, ○ Frequent handwashing and disinfection of surfaces causing shock B. SEXUALLY TRANSMITTED INFECTIONS (STI) Endotoxins Lipopolysaccharides that are part of Infections that have sexual contact as means of the outer membrane of gram-negative transmission bacteria. Risk factors: Toxin is released with cell lysis and ○ Homosexuality their effects are generalized (general ○ Unsafe sexual practices systemic effects). ○ Injection drug use Can cause widespread endothelial ○ Sexual abuse: suspect in children with evidence of dysfunction leading to septic shock, STI-associated infections disseminated intravascular coagulation, ○ Unconventional sexual practices e.g., oral-anal sex and adult respiratory distress syndrome Important general principles: Immune Immune reactions cause inflammation ○ Unique; as infection with one STI-associated Damage that cause tissue injury. organism increases the risk for other or additional These are some of the mechanisms by STIs which bacteria can cause This is because genital mucosal damage from immune-mediated tissue damage: one infection facilitates entry of other organisms Immune Immune complexes composed of bacterial ○ Microbes that can cause STIs can exhibit or is Complex antigens can get deposited into tissues and capable of vertical transmission and can cause Formation trigger inflammation and tissue injury. disease: E.g., Post-streptococcal glomerulo- Common during vaginal delivery, when the nephritis (PSAGN) caused by S. baby gets exposed to active genital lesions pyogenes E.g., Perinatal transmission of Neisseria ○ Streptococcal antigens get planted gonorrhoeae and Chlamydia trachomatis can in the glomeruli and form immune cause conjunctivitis complexes that trigger inflammation E.g., Perinatal transmission of HSV can cause causing glomerular injury encephalitis ○ STIs may become established locally and spread to Immune Some bacterial antigens bear significant other structures (causing greater morbidity) Cross- homology to our self antigens and so our E.g., In pelvic inflammatory disease, urethral reactions immune system also attacks our own tissues. Neisseria or Chlamydial tract infection may E.g., Acute rheumatic fever caused by ascend to the upper female genital tract S. pyogenes ○ Streptococcal M proteins mimic cardiac self-antigens, causing the Pathology - Mod 5 Host-Pathogen Interaction 6 of 8 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited. C. OPPORTUNISTIC INFECTIONS can cause markedly low neutrophil Infections caused by organisms that will not cause counts disease in patients with robust immune system or intact defense mechanisms Require immune compromise which can happen in Immuno- Patients on glucocorticoids (steroids), different settings: suppressive transplant patients, and cancer therapy patients (bone marrow suppression as side effect of chemotherapy) Innate Immunity 1 Phagocyte and complement Deficiency Other Cystic fibrosis: patients have impaired medical clearance of secretions Adaptive Immunity 2 Humoral and cell-mediated conditions Susceptible to respiratory infections Deficiency caused by Pseudomonas Iatrogenic aeruginosa, S. aureus, and immunosuppression Burkholderia cepacia 3 Other Conditions Sickle cell anemia: Longstanding Other medical conditions Malnutrition disease causes fibrous atrophy of the spleen Susceptible to encapsulated Deficiency in innate immunity or adaptive immunity may organisms like S. pneumoniae be either primary involving genetic mutations or secondary such as in HIV. Malnutrition Lack of building blocks to produce and Transplant patients should also be wary of infectious maintain host defenses complications because they are required to take immunosuppressive drugs for their body to tolerate the transplanted organ. V. SUMMARY Cancer patients on chemotherapy are also prone to The outcome of an infection depends on the balance infections because some drugs can cause suppression between the pathogen’s virulence and the nature and of the bone marrow and low white blood cell counts. magnitude of the host immune response. Other medical conditions such as cystic fibrosis, sickle Pathogens can either alter themselves or their cell anemia, and malnutrition can cause immune environment in order to escape the host immune system deficiency that can lead to opportunistic infections. and cause infection. The response to infection is inflammation that can take MECHANIS DETAILS/EXAMPLES many patterns depending on the type of pathogen and M host immune response. There are different mechanisms by which organisms can cause disease. Antibody X-linked Bruton agammaglobulinemia: There are special types of infections with unique deficiency absence of B-cells, plasma cells, and implications to management. (Humoral antibodies adaptive Increased susceptibility to infection immunity) by EXTRACELLULAR microbes like S. aureus, S. pneumoniae, H. influenzae and some viruses like rotavirus and enterovirus T-cell DiGeorge syndrome: thymic hypoplasia deficiency → decreased T cells (Cell- mediated HIV: progressive decline in CD4+ T cells adaptive Increased susceptibility to immunity) INTRACELLULAR pathogens like viruses, fungi, and parasites Deficiency C3 deficiency: increased susceptibility to in pyogenic organisms complement proteins C5-C9 deficiency: increased susceptibility to Neisseria infections Deficient Deficient function: chronic neutrophil granulomatous disease number and Inadequate oxidative burst causes function increased susceptibility to infections by Catalase-positive organisms (S. aureus) Deficient number Leukemia: impaired white blood cell production because of marrow infiltration by leukemic cells Agranulocytosis: some drugs (cancer chemotherapy, antibiotics) Pathology - Mod 5 Host-Pathogen Interaction 7 of 8 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  HOST’S INFLAMMATORY RESPONSE TO INFECTION ETIOLOGIC CLUES PATTERN MORPHOLOGIC CLUES (Think of…) Suppurative (Purulent) Pyogenic bacteria Acute inflammation Infection (S. aureus, S. pyogenes) Liquefactive necrosis Lymphocytes Mononuclear Acute viral or long-standing infections Macrophages Plasma cells Hard to eliminate organisms Granulomatous Granulomas (TB, fungi, parasite eggs) Inclusions Cytopathic/ Viruses (because they infect cells and cause changes) Multinucleation Cytoproliferative Tumors Coagulative and liquefactive necrosis Toxin-producing bacteria Tissue Necrosis (gangrenous) (Clostridium perfringens, Corynebacterium diphtheriae) They can also produce abscesses Chronic Inflammation/ Fibrosis Long-standing infections Scarring Parenchymal loss No Reaction Severe immunodeficiency Organisms present with little inflammation IMMUNODEFICIENCY AND OPPORTUNISTIC INFECTIONS TYPES DETAILS Leukemia Drugs Leukocyte Number ○ Cancer chemotherapy ○ Antibiotics Innate immunity deficiency Chronic granulomatous disease Leukocyte Function Leukocyte adhesion deficiency Pyogenic organisms (C3) Complement Deficiency Neisseria infections (C5-C9) Humoral Bruton agammaglobulinemia (X-linked) Adaptive immunity deficiency DiGeorge Syndrome (Primary) Cell-mediated HIV (Secondary) Chemotherapy Immunosuppressive therapy Transplant medications Steroids Other Conditions Cystic fibrosis Medical conditions Sickle cell anemia Malnutrition Pathology - Mod 5 Host-Pathogen Interaction 8 of 8 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.