VIRAL PATHOGENESIS AND HOST IMMUNE RESPONSES Claude MUVUNYI M.D., Ph.D.

Viruses and host cell interactions Viruses cause disease after : – they break through the natural protective barriers of the body, – evade immune control and either kill cells of an important tissue or trigger a destructive immune and inflammatory response. The majority of viral infections are subclinical. It is not in the interest of the virus to severely harm or kill the host. The outcome of a viral infection is determined by: – the nature of the virus-host interaction – the host response to the infection.

Factors in Viral Pathogenesis Effects of viral infection on cells (Cellular Pathogenesis) Entry into the Host Course of Infection (Primary Replication, Systemic Spread, Secondary Replication) Cell/Tissue Tropism Cell/Tissue Damage Host Immune Response Virus Clearance or Persistence

Viral Entry Skin - Most viruses which infect via the skin require a breach in the physical integrity of this effective barrier, e.g. cuts or abrasions. Many viruses employ vectors, e.g. ticks, mosquitos or vampire bats to breach the barrier. Conjunctiva and other mucous membranes - rather exposed site and relatively unprotected Respiratory tract - In contrast to skin, the respiratory tract and all other mucosal surfaces possess sophisticated immune defence mechanisms, as well as non-specific inhibitory mechanisms (cilliated epithelium, mucus secretion, lower temperature) which viruses must overcome. Gastrointestinal tract - a hostile environment; gastric acid, bile salts, etc. Viruses that spread by the GI tract must be adapted to this hostile environment. Genitourinary tract - relatively less hostile than the above, but less frequently exposed to extraneous viruses (?)

Course of Viral Infection Primary Replication – The place of primary replication is where the virus replicates after gaining initial entry into the host. – This frequently determines whether the infection will be localized at the site of entry or spread to become a systemic infection. Systemic Spread – Apart from direct cell-to-cell contact, the virus may spread via the blood stream and the CNS. Secondary Replication – Secondary replication takes place at susceptible organs/tissues following systemic spread.

Outcome of Viral Infection Acute Infection – Recovery with no residue effects – Recovery with residue effects e.g. acute viral encephalitis leading to neurological sequelae. – Death – Proceed to chronic infection Chronic Infection – Silent subclinical infection for life e.g. CMV, EBV – A long silent period before disease e.g. HIV, SSPE, PML – Reactivation to cause acute disease e.g. herpes and shingles. – Chronic disease with relapses and excerbations e.g. HBV, HCV. – Cancers e.g. EBV, HTLV-1, HPV, HBV, HCV, HHV-8

Clinical latency

Host Defenses against viral infections The immune response to the virus probably has the greatest impact on the outcome of infection. In the most cases, the virus is cleared completely from the body and results in complete recovery. In other infections, the immune response is unable to clear the virus completely and the virus persists. In a number of infections, the immune response plays a major pathological role in the disease. In general, cellular immunity plays the major role in clearing virus infection whereas humoral immunity protects against reinfection.

Host Defenses against viral infections Humans are protected from viral infection by: – Natural barriers (e.g., skin, mucus ciliated epithelium, gastric acis, bile), – Nonspecific immune defenses (fever, interferon, macrophage, natural killer cells), and – Antigen-specific immune responses (e.g., antibodies, T cells activities). Both humoral and cellular immune responses, of specific immunity, are important to antiviral immunity

Host Defenses against viral infections Interferon's block local viral replication and initiate the antiviral state in surrounded cells Natural killer cells target and kill directly virus-infected cells (especially enveloped viruses) Macrophages filter viral particles and infected target cells from blood, engulf them for processing and presenting viral antigens to CD 4 T cells and CD 8 T cells T cells are essential to control viral infection and recognize viral antigens on cell surfaces. – T helper, CD 4 lymphocytes are the “orchestral chief” of the immune response because they excrete cytokines which controle all the reactions of immune system. – T cytolytic CD 8 lymphocytes can directly lyse target infected cells.

Host Defenses against viral infections Cell-mediated immunity is required for lysis of the target cells in the settings of non-cytolytic infections, e.g., hepatitis A, B or C. Indeed Hepatitis A, B and C virus are noncytolytic causing an exacerbation of immune response without killing of they infected cells ntibodies neutralize extracellular viruses. Antiboies may be sufficient to control cytolytic viruses, because the virion factor of the infected cell is eliminated by viral replication.

13 Persistent Infections - 1 Persistent infections usually represent a secondary event, following on from an initial acute infection. Persistent infections are not usually significant causes of acute illness, but they are important for five reasons: i.They enable the infectious agent to persist in the community ii.They can be activated in immunosuppressed patients iii.Some are associated with immunopathological disease iv.Some are associated with neoplasms v.Some are immunosuppressive (HIV) and permit disease caused by other normally harmless persistent microorganisms Persistent infections cannot by definition be acutely lethal, in fact they tend to cause only mild tissue damage or disease in the host

14 2 types of persistent infections i.chronic viral infections characterized by continuous shedding of the virus for prolonged periods of time. congenital infections with rubella virus or cytomegalovirus (CMV) chronic infections with HBV or HCV associated disease may be as a consequence of progressive injury to the host tissues or by immune-mediated destruction of virus-infected cells. ii.latent viral infections characterized by the maintenance of the viral genome in host cells in the absence of viral replication. herpesviruses and retroviruses associated disease usually as a consequence of reactivation of productive infection with subsequent cytopathogenicity or alteration of cell-cycle control mechanisms leading to neoplasia. The distinction between chronic and latent infection is not always readily apparent for some viruses e.g. HIV Persistent Infections - 2

15 Viruses causing persistent infections must be able to evade the host immune system and have a mechanism to attenuate their virulence. Preferred sites for establishment of persistent viral infections neurons (e.g. HSV, VZV, measles virus, poliovirus, JC virus) liver (e.g. HBV, HCV) lymphocytes or monocytes (e.g. CMV, EBV, HIV, HTLV) CNS can be a preferred site for persistent viral infection since it is not readily accessible by the immune system. Persistent Infections - 3

16 Persistent infections: failure to eliminate microbe

17 Mechanisms of Viral Persistence- 1 There are many strategies that microorganisms have evolved to by-pass or overcome host defenses: 1.tolerance 2.immunosuppression 3.antiphagocytic strategies 4.absence of suitable target for the immune system 5.“mopping up” antibodies 6.interference with immune forces 7.antigenic variation 8.reduced interferon induction or responsiveness 9.microbial presence in inaccessible sites 10.“invade the immune system, evade the immune system”

18 Mechanisms of Viral Persistence- 2 1.Tolerance: immunologically specific reduction in the immune response to a given antigen (ie lack of responsiveness) Molecular mimicry - microbial Ag is similar to host Ag so immune response to this Ag is weak 2.Immunosuppression: host shows depressed immune response to antigens unrelated to those of the infecting organism. Infectious agents that multiply in macrophages or lymphoid tissue (e.g. many viruses including measles, mumps, influenza, EBV, CMV, HIV) are especially likely to cause immunosuppression. HIV infects both CD4+ T cells and macrophages resulting in loss of immune reactivity, particularly T helper function.

19 3.Microbial adaptations to the encounter with the phagocytic cell Microorganisms first exposed to the phagocytes. Microorganisms which attract, are ingested, and killed by phagocytes fail to cause a successful infection. Most successful microorganisms have evolved to some degree to either avoid phagocytes or interfere with antimicrobial activities of the phagocytes. Most viruses do not infect phagocytes, but the following viruses do multiply in macrophages (entry via endocytosis or fusion, not phagocytosis): Herpes viruses Measles virus Poxvirus Mechanisms of Viral Persistence- 3

20 Phagocytosis and intracellular digestion

21 Antiphagocytic strategies

22 Mechanisms of Viral Persistence- 4 4.Absence of suitable target for immune response Intracellular microorganisms evade immune response within infected cells (e.g. HSV and VZV persistent infection in dorsal root ganglion cells, and EBV in circulating lymphocytes) Direct cell to cell spread (not extracellular) HSV spreads in presence of neutralizing Ab Some enveloped viruses (corona and flaviviruses) avoid displaying Ags on cell surface by budding into cytoplasmic vesicles - virion release via fusion of vesicle and plasma membrane. 5.Antibodies mopped up by soluble microbial antigens Hepatitis B virus - HBsAg is present in serum of carriers at per mL 6.Local interference with immune forces Viruses causing latent infections can evade Ab and CMI responses by decreasing viral protein expression. Herpes viruses encode genes which interfere with immune system function Adenovirus E3/19K protein blocks cell surface expression of MHC class I proteins – diminished presentation of viral Ags to cytotoxic T cells. CMV US11 gene product downregulates MHC class I proteins by targeting these molecules to proteosomes for degradation.

23 Mechanisms of Viral Persistence- 5 7.Antigenic variation allows escape from neutralizing Abs HIV - persistent infection, shows antigenic variation Influenza viruses - antigenic shift, antigenic drift 8.Reduced interferon induction or responsiveness Interferon - cytokines which influence the function of T cells by increasing the expression of MHC proteins and also have antiviral activity. Viruses are generally sensitive to interferon - evasion by failing to induce IFN production in the host or if they are resistant to action of interferon Vaccinia virus - secretes a soluble receptor which binds and inactivates IFN Adenovirus - insensitive to IFN HBV - poor IFN inducer

24 9.Microbial presence in sites inaccessible to the immune response Many viruses persist in the infected host and are shed to the exterior via the saliva (HSV, CMV), milk (CMV) or urine (polyomavirus in mice) and are therefore only exposed on the lumen of the salivary gland, mammary gland or kidney tubule. It is difficult for T cells and Ab to reach the lumen and eliminate the infection. 10.“Invade the immune system, evade the immune system” Infection of lymphoreticular tissues by viruses exhibiting systemic infection or persistence: Adenovirus (lymphocytes) Epstein-Barr virus (lymphocytes) Cytomegalovirus (macrophages) Measles virus (lymphocytes) Rubella virus (lymphocytes and macrophages) HIV (lymphocytes and macrophages) Mechanisms of Viral Persistence- 6

Summary Viral Pathogenesis depends on the complex interplay of a large number of viral and host factors. Viral factors include cell tropism and cellular pathogenesis. The immune response is the most important host factor, as it determines whether the virus is cleared or not. – After the virus penetrate the natural barriers, it activate nonspecific immune defenses, which attempt to limit and control the local viral replication and spread. – Antigen-specific immune responses or specific immune defenses are the last to be activated and are generally systematic The immune response is the best, in most cases the only and sufficient, mean of controlling a viral infection.