Infection and immunity (Proceedings)

The primary role of the immune system is to protect against infectious disease. The mechanisms employed vary in efficiency for intra- vs extracellular pathogens. Nonspecific immunologic resistance involves interferon – stimulates production of proteins with antiviral activity. It is produced by infected cell, released, bind cell receptor on adjacent cells to induce "antiviral state" – it blocks virus transcription, interferes with virus replication at several levels, and enhances immune response (γ). Specific immunity involves both antibody – blocks attachment and/or penetration; opsonizes; complement-mediated lysis; clumping – and cell mediated immunity, which is most important; TC-mediated destruction of virus-infected cells. For bacteria, innate resistance is important as well – physical barriers, enzymes, lactoferrin, complement; macrophages and neutrophils are also critical. The macrophages and dendritic cells in particular are important not only for bacterial destruction, but activation of T helper lymphocytes as well through antigen presentation. Antibodies from B lymphocytes neutralizes toxins; opsonization; and complement activation. CMI is important for intracellular bacteria.

Canine distemper virus (CDV) causes canine distemper, and infects a variety of different cell types, including epithelial, mesenchymal, neuroendocrine, and hematopoietic cells, the marked tropism of CDV for immune cells is critical in respect to its ability to cause immunosuppression. The virus initially infects monocytes within lymphoid tissue in the upper respiratory tract and tonsils, and is subsequently disseminated via the lymphatics and blood to the entire reticuloendothelial system. Direct viral destruction of a significant proportion of the lymphocyte population, and especially CD4+ T cells, occurs within the blood, tonsils, thymus, spleen, lymph nodes, bone marrow, mucosa-associated lymphoid tissue and the hepatic Kuppfer cells. This is associated with an initial lymphopenia and transient fever, which occurs a few days after infection. Subsequently there is a second stage of cell-associated viremia, after which CDV infects cells of the lower respiratory, gastrointestinal tract, central nervous system, urinary tract, as well as red and white blood cells, including additional lymphoid cells. Infection of dendritic cells within the thymus may lead to impaired maturation and selection of T cells, with subsequent release of immature CD5- T cells, including cells that may have the potential for autoreactivity.

Canine Parvovirus induces a leukopenia, along with disruption of the gastrointestinal barrier, and the immature immune system of the young animals which may lead to the development of sepsis. Both CPV and FPV have tropism for rapidly-dividing cells. As such, they exert an effect on the host that resembles the outcome of treatment with a chemotherapeutic drug. Immunosuppression may also contribute to replication of other coinfecting enteric viruses, such as enteric coronavirus, which in turn exacerbate the damage to the gastrointestinal mucosa.

As a result of its T-cell tropism, FeLV-T infection may be particularly associated with immunodeficiency in cats. The immunosuppressive properties of FeLV have been linked at least in part to the transmembrane viral envelope peptide, p15E. This viral protein inhibits T and B cell function, inhibits cytotoxic lymphocyte responses, alters monocyte morphology and distribution, and has been associated with impaired cytokine production and responsiveness. CD4+ T cell malfunction may contribute to a decreased humoral and cellular immune response in affected cats. Neutrophil function has also been shown to be impaired in FeLV-infected cats.

Central to FIV-induced immunosuppression is a progressive reduction in CD4+ T cell numbers. Evidence also points to altered dendritic cell function during acute FIV infection. The impairment of T cell function in acute FIV infection has been suggested to result from cytokine dysregulation, immunologic anergy and increased apoptosis. In turn, this is associated with an inability to mount a primary immune response to opportunistic pathogens. Ultimately, these changes lead to opportunistic infections.

Feline coronavirus infection is associated with a depletion of CD4+ and CD8+ cells, as well as a hypergammaglobulinemia, suggesting virus-induced dysregulation of the immune response. The mechanism of T cell depletion is not clear, as the virus does not infect lymphocytes, only monocytes and macrophages. Infection of antigen-presenting cells, specifically dendritic cells, by the virus, has been hypothesized to cause T cell apoptosis. Despite the profound T cell deficiency that accompanies FIP, opportunistic infections are rarely reported, partly perhaps as a result of the rapidly fatal clinical course of disease.

Bacterial infections causing immunodeficiency include those of the tick-borne pathogens Ehrlichia canis and Anaplasma phagocytophilum. Ehrlichia canis is a gram negative intracellular bacteria that causes canine monocytic ehrlichiosis (CME). The organism infects monocytes, in which it forms morulae. The chronic phase may also be associated with development of secondary opportunistic infections. The precise underlying mechanism of the immunodeficiency that develops, and how it relates to successful persistence of E. canis, has not yet been elucidated. In contrast to E. canis which infects monocytes, A. phagocytophilum infects granulocytes, primarily the neutrophil, and causes granulocytic anaplasmosis. Immunosuppression resulting from A. phagocytophilum infection results primarily from impairment of neutrophil function by the bacteria. A. phagocytophilum also reduces neutrophil mobility and phagocytosis, and reduces endothelial adherence and transmigration of neutrophils.

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