DNA viruses often persist in the body of their host, becoming latent and recurring many months or years later. By contrast, most RNA viruses cause acute infections that are cleared from the host as ...they lack the mechanisms to persist. However, it is becoming clear that viral RNA can persist after clinical recovery and elimination of detectable infectious virus. This persistence can either be asymptomatic or associated with late progressive disease or nonspecific lingering symptoms, such as may be the case following infection with Ebola or Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Why does viral RNA sometimes persist after recovery from an acute infection? Where does the RNA come from? And what are the consequences?
Measles is an acute systemic viral infection with immune system interactions that play essential roles in multiple stages of infection and disease. Measles virus (MeV) infection does not induce type ...1 interferons, but leads to production of cytokines and chemokines associated with nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) signaling and activation of the NACHT, LRR and PYD domains-containing protein (NLRP3) inflammasome. This restricted response allows extensive virus replication and spread during a clinically silent latent period of 10-14 days. The first appearance of the disease is a 2-3 day prodrome of fever, runny nose, cough, and conjunctivitis that is followed by a characteristic maculopapular rash that spreads from the face and trunk to the extremities. The rash is a manifestation of the MeV-specific type 1 CD4⁺ and CD8⁺ T cell adaptive immune response with lymphocyte infiltration into tissue sites of MeV replication and coincides with clearance of infectious virus. However, clearance of viral RNA from blood and tissues occurs over weeks to months after resolution of the rash and is associated with a period of immunosuppression. However, during viral RNA clearance, MeV-specific antibody also matures in type and avidity and T cell functions evolve from type 1 to type 2 and 17 responses that promote B cell development. Recovery is associated with sustained levels of neutralizing antibody and life-long protective immunity.
Measles is an important cause of child mortality that has a seemingly paradoxical interaction with the immune system. In most individuals, the immune response is successful in eventually clearing ...measles virus (MV) infection and in establishing life-long immunity. However, infection is also associated with persistence of viral RNA and several weeks of immune suppression, including loss of delayed type hypersensitivity responses and increased susceptibility to secondary infections. The initial T-cell response includes CD8⁺ and T-helper 1 CD4⁺ T cells important for control of infectious virus. As viral RNA persists, there is a shift to a T-helper 2 CD4⁺ T-cell response that likely promotes B-cell maturation and durable antibody responses but may suppress macrophage activation and T-helper 1 responses to new infections. Suppression of mitogen-induced lymphocyte proliferation can be induced by lymphocyte infection with MV or by lymphocyte exposure to a complex of the hemagglutinin and fusion surface glycoproteins without infection. Dendritic cells (DCs) are susceptible to infection and can transmit infection to lymphocytes. MV-infected DCs are unable to stimulate a mixed lymphocyte reaction and can induce lymphocyte unresponsiveness through expression of MV glycoproteins. Thus, multiple factors may contribute both to measles-induced immune suppression and to the establishment of durable protective immunity.
Measles remains an important cause of child morbidity and mortality worldwide despite the availability of a safe and efficacious vaccine. The current measles virus (MeV) vaccine was developed ...empirically by attenuation of wild-type (WT) MeV by in vitro passage in human and chicken cells and licensed in 1963. Additional passages led to further attenuation and the successful vaccine strains in widespread use today. Attenuation is associated with decreased replication in lymphoid tissue, but the molecular basis for this restriction has not been identified. The immune response is age dependent, inhibited by maternal antibody (Ab) and involves induction of both Ab and T cell responses that resemble the responses to WT MeV infection, but are lower in magnitude. Protective immunity is correlated with levels of neutralizing Ab, but the actual immunologic determinants of protection are not known. Because measles is highly transmissible, control requires high levels of population immunity. Delivery of the two doses of vaccine needed to achieve >90% immunity is accomplished by routine immunization of infants at 9-15 months of age followed by a second dose delivered before school entry or by periodic mass vaccination campaigns. Because delivery by injection creates hurdles to sustained high coverage, there are efforts to deliver MeV vaccine by inhalation. In addition, the safety record for the vaccine combined with advances in reverse genetics for negative strand viruses has expanded proposed uses for recombinant versions of measles vaccine as vectors for immunization against other infections and as oncolytic agents for a variety of tumors.
The disease spectrum of coronavirus disease 2019 (COVID-19) ranges from no symptoms to multisystem failure and death. Characterization of virus-specific immune responses to severe acute respiratory ...coronavirus 2 (SARS-CoV-2) is key to understanding disease pathogenesis, but few studies have evaluated T cell immunity. In this issue of the JCI, Sattler and Angermair et al. sampled blood from subjects with COVID-19 and analyzed the activation and function of virus antigen-specific CD4+ T cells. T cells that failed to respond to peptides from the membrane, spike, or nucleocapsid proteins were more common in subjects who died. In those whose T cells had the capacity to respond, older patients with comorbidity had larger numbers of activated T cells compared with patients who had fewer risk factors, but these cells showed impaired IFN-γ production. This cross-sectional study relates activated T cell responses to patient risk factors and outcome. However, T cell response trajectory over the disease course remains an open question.
Measles Moss, William J, Dr; Griffin, Diane E, MD
The Lancet (British edition),
01/2012, Volume:
379, Issue:
9811
Journal Article
Peer reviewed
Summary Measles is a highly contagious disease caused by measles virus and is one of the most devastating infectious diseases of man—measles was responsible for millions of deaths annually worldwide ...before the introduction of the measles vaccines. Remarkable progress in reducing the number of people dying from measles has been made through measles vaccination, with an estimated 164 000 deaths attributed to measles in 2008. This achievement attests to the enormous importance of measles vaccination to public health. However, this progress is threatened by failure to maintain high levels of measles vaccine coverage. Recent measles outbreaks in sub-Saharan Africa, Europe, and the USA show the ease with which measles virus can re-enter communities if high levels of population immunity are not sustained. The major challenges for continued measles control and eventual eradication will be logistical, financial, and the garnering of sufficient political will. These challenges need to be met to ensure that future generations of children do not die of measles.
Measles immunity and immunosuppression Griffin, Diane E
Current opinion in virology,
February 2021, 2021-Feb, 2021-02-00, 20210201, Volume:
46
Journal Article
Peer reviewed
Open access
•Measles virus replication in lymphoid tissue uses CD150 as a B and T cell receptor.•Persistent RNA in lymphoid tissue is associated with generation of durable immunity.•Germinal centers and numbers ...of peripheral Tfh cells and antibody-secreting cells increase for months.•Increased susceptibility to other infections continues for years after apparent recovery.•Memory and naïve B cells are depleted and diversity of pre-existing antibodies is reduced.
Effects of measles on the immune system are only partially understood. Lymphoid tissue is a primary site of measles virus (MeV) replication where CD150 is the receptor for infection of both B and T cells. Lymphocyte depletion occurs during the acute phase of infection, but initiation of the adaptive immune response leads to extensive lymphocyte proliferation, production of MeV-specific antibody and T cells, the rash and clearance of infectious virus. Viral RNA persists in lymphoid tissue accompanied by ongoing germinal center proliferation, production of antibody-secreting cells, functionally distinct populations of T cells and antibody avidity maturation to establish life-long immunity. However, at the same time diversity of pre-existing antibodies and numbers of memory and naive B cells are reduced and susceptibility to other infections is increased.
•In immunocompromised patients failure of measles virus clearance may lead to progressive lung or nervous system disease.•Children infected at a young age may develop subacute sclerosing ...panencephalitis, a progressive nervous system disease many years later.•Slow clearance of measles virus RNA from lymphoid tissue is associated with maturation of immune responses and life long immunity.•Slow clearance of measles virus RNA from lymphoid tissue may impair new immune responses and increase susceptibility to other infections.
Clearance of measles virus is complex. Infectious virus is cleared by the adaptive immune response manifested by the characteristic maculopapular rash. CD8+ T cells are major effectors of infectious virus clearance, a process that may fail in individuals with compromised cellular immune responses leading to progressive giant cell pneumonia and/or measles inclusion body encephalitis. In contrast to the usual rapid clearance of infectious virus, clearance of viral RNA is slow with persistence in lymphoid tissue for many months. Persistence of MeV RNA may contribute to the late development of the slowly progressive disease subacute sclerosing panencephalitis in children infected at a young age and to measles-associated immune suppression but also to maturation of the immune response and development of life-long immunity.
A wide range of viruses from different virus families in different geographical areas, may cause immediate or delayed neuropathological changes and neurological manifestations in humans and animals. ...Infection by neurotropic viruses as well as the resulting immune response can irreversibly disrupt the complex structural and functional architecture of the central nervous system, frequently leaving the patient or affected animal with a poor or fatal prognosis. Mechanisms that govern neuropathogenesis and immunopathogenesis of viral infections are highlighted, using examples of well-studied virus infections that are associated with these alterations in different populations throughout the world. A better understanding of the molecular, epidemiological and biological characteristics of these infections and in particular of mechanisms that underlie their clinical manifestations may be expected to provide tools for the development of more effective intervention strategies and treatment regimens.
•Persistent infections as reservoirs of infection and RNA virus epidemiology.•Disease and immune consequences of persistent RNA virus infections.•The role of host responses and virus mechanisms in ...the establishment of persistent infections.
In a prototypical response to an acute viral infection it would be expected that the adaptive immune response would eliminate all virally infected cells within a few weeks of infection. However many (non-retrovirus) RNA viruses can establish ‘within host’ persistent infections that occasionally lead to chronic or reactivated disease. Despite the importance of ‘within host’ persistent RNA virus infections, much has still to be learnt about the molecular mechanisms by which RNA viruses establish persistent infections, why innate and adaptive immune responses fail to rapidly clear these infections, and the epidemiological and potential disease consequences of such infections.
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