Biomedical subjects

Mark K Slifka

Publications and source records attributed to Mark K Slifka.

24 records · Page 2Linked to original sources

PubMed2004

How do viral infections predispose patients to bacterial infections?

PURPOSE OF REVIEW: Bacterial sepsis is a leading cause of death in the United States, accounting for over 200,000 fatalities annually. Approximately half of bacterial sepsis cases occur following acute respiratory infections, and the lungs are the most common organs to fail. Notably, outbreaks of respiratory viral infections are associated with an increased incidence or severity of bacterial co-infections, with normally innocuous infections often becoming fatal. Understanding the 'lethal synergism' associated with concomitant infections may point the way toward improved anti-sepsis treatments. RECENT FINDINGS: Murine models of viral and bacterial co-infection mimic the lethal synergism observed in humans and reveal at least two mechanisms of interaction. First, bacterial infiltration is heightened during acute viral infection. Secondly, the nature of responding cell populations is dramatically altered during concomitant infections. Although natural killer cells and macrophages are predominant cell populations responding to bacterial infection in a naïve host, there is also a large T cell component that is activated upon viral infection. Inflammatory cytokines produced by these cells contribute to lethal immunopathology, and therapeutic strategies need to target the initial causative microbes as well as subsequent inflammatory responses. Current therapies directed only at the host immune response have not been overly successful, owing largely to difficulties in reversing the severe immunopathology associated with sepsis. SUMMARY: Respiratory viral infections may facilitate secondary bacterial infections and increase host immunopathology through the overproduction of inflammatory cytokines. Preventive measures, including vaccination and aggressive antimicrobial therapy early in the course of infection, may significantly reduce the morbidity and mortality of sepsis.

Animals↗

PubMed2003

Duration of antiviral immunity after smallpox vaccination.

Although naturally occurring smallpox was eliminated through the efforts of the World Health Organization Global Eradication Program, it remains possible that smallpox could be intentionally released. Here we examine the magnitude and duration of antiviral immunity induced by one or more smallpox vaccinations. We found that more than 90% of volunteers vaccinated 25-75 years ago still maintain substantial humoral or cellular immunity (or both) against vaccinia, the virus used to vaccinate against smallpox. Antiviral antibody responses remained stable between 1-75 years after vaccination, whereas antiviral T-cell responses declined slowly, with a half-life of 8-15 years. If these levels of immunity are considered to be at least partially protective, then the morbidity and mortality associated with an intentional smallpox outbreak would be substantially reduced because of pre-existing immunity in a large number of previously vaccinated individuals.

Adult↗

PubMed2003

Preferential escape of subdominant CD8+ T cells during negative selection results in an altered antiviral T cell hierarchy.

Negative selection is designed to purge the immune system of high-avidity, self-reactive T cells and thereby protect the host from overt autoimmunity. In this in vivo viral infection model, we show that there is a previously unappreciated dichotomy involved in negative selection in which high-avidity CD8(+) T cells specific for a dominant epitope are eliminated, whereas T cells specific for a subdominant epitope on the same protein preferentially escape deletion. Although this resulted in significant skewing of immunodominance and a substantial depletion of the most promiscuous T cells, thymic and/or peripheral deletion of high-avidity CD8(+) T cells was not accompanied by any major change in the TCR V beta gene family usage or an absolute deletion of a single preferred complementarity-determining region 3 length polymorphism. This suggests that negative selection allows high-avidity CD8(+) T cells specific for subdominant or cryptic epitopes to persist while effectively deleting high-avidity T cells specific for dominant epitopes. By allowing the escape of subdominant T cells, this process still preserves a relatively broad peripheral TCR repertoire that can actively participate in antiviral and/or autoreactive immune responses.

Animals↗

PubMed2003

Measles virus infection results in suppression of both innate and adaptive immune responses to secondary bacterial infection.

Among infectious agents, measles virus (MV) remains a scourge responsible for 1 million deaths per year and is a leading cause of childhood deaths in developing countries. Although MV infection itself is not commonly lethal, MV-induced suppression of the immune system results in a greatly increased susceptibility to opportunistic bacterial infections that are largely responsible for the morbidity and mortality associated with this disease. Despite its clinical importance, the underlying mechanisms of MV-induced immunosuppression remain unresolved. To begin to understand the basis of increased susceptibility to bacterial infections during MV infection, we inoculated transgenic mice expressing the MV receptor, CD46, with MV and Listeria monocytogenes. We found that MV-infected mice were more susceptible to infection with Listeria and that this corresponded with significantly decreased numbers of macrophages and neutrophils in the spleen and substantial defects in IFN-gamma production by CD4(+) T cells. The reduction in CD11b(+) macrophages and IFN-gamma-producing T cells was due to reduced proliferative expansion and not to enhanced apoptosis or to altered distribution of these cells between spleen, blood, and the lymphatic system. These results document that MV infection can suppress both innate and adaptive immune responses and lead to increased susceptibility to bacterial infection.

Animals↗

PubMed2002

Immunodominance in virus-induced CD8(+) T-cell responses is dramatically modified by DNA immunization and is regulated by gamma interferon.

The phenomenon whereby the host immune system responds to only a few of the many possible epitopes in a foreign protein is termed immunodominance. Immunodominance occurs not only during microbial infection but also following vaccination, and clarification of the underlying mechanism may permit the rational design of vaccines which can circumvent immunodominance, thereby inducing responses to all epitopes, dominant and subdominant. Here, we show that immunodominance affects DNA vaccines and that the effects can be avoided by the simple expedient of epitope separation. DNA vaccines encoding isolated dominant and subdominant epitopes induce equivalent responses, confirming a previous demonstration that coexpression of dominant and subdominant epitopes on the same antigen-presenting cell (APC) is central to immunodominance. We conclude that multiepitope DNA vaccines should comprise a cocktail of plasmids, each with its own epitope, to allow maximal epitope dispersal among APCs. In addition, we demonstrate that subdominant responses are actively suppressed by dominant CD8(+) T-cell responses and that gamma interferon (IFN-gamma) is required for this suppression. Furthermore, priming of CD8(+) T cells to a single dominant epitope results in strong suppression of responses to other normally dominant epitopes in immunocompetent mice, in effect rendering these epitopes subdominant; however, responses to these epitopes are increased 6- to 20-fold in mice lacking IFN-gamma. We suggest that, in agreement with our previous observations, IFN-gamma secretion by CD8(+) T cells is highly localized, and we propose that its immunosuppressive effect is focused on the APC with which the dominant CD8(+) T cell is in contact.

Animals↗

PubMed2002

Cell cycle status affects coxsackievirus replication, persistence, and reactivation in vitro.

Enteroviral persistence has been implicated in the pathogenesis of several chronic human diseases, including dilated cardiomyopathy, insulin-dependent diabetes mellitus, and chronic inflammatory myopathy. However, these viruses are considered highly cytolytic, and it is unclear what mechanisms might permit their long-term survival. Here, we describe the generation of a recombinant coxsackievirus B3 (CVB3) expressing the enhanced green fluorescent protein (eGFP), which we used to mark and track infected cells in vitro. Following exposure of quiescent tissue culture cells to either wild-type CVB3 or eGFP-CVB3, virus production was very limited but increased dramatically after cells were permitted to divide. Studies with cell cycle inhibitors revealed that cells arrested at the G(1) or G(1)/S phase could express high levels of viral polyprotein and produced abundant infectious virus. In contrast, both protein expression and virus yield were markedly reduced in quiescent cells (i.e., cells in G(0)) and in cells blocked at the G(2)/M phase. Following infection with eGFP-CVB3, quiescent cells retained viral RNA for several days in the absence of infectious virus production. Furthermore, RNA extracted from nonproductive quiescent cells was infectious when transfected into dividing cells, indicating that CVB3 appears to be capable of establishing a latent infection in G(0) cells, at least in tissue culture. Finally, wounding of infected quiescent cells resulted in viral protein expression limited to cells in and adjacent to the lesion. We suggest that (i) cell cycle status determines the distribution of CVB3 during acute infection and (ii) the persistence of CVB3 in vivo may rely on infection of quiescent (G(0)) cells incapable of supporting viral replication; a subsequent change in the cell cycle status may lead to virus reactivation, triggering chronic viral and/or immune-mediated pathology in the host.

Cell Cycle↗