TOPICS

HOT TOPICS IN EIA RESEARCH

Disease Pathogenesis

 

The following will appear in the Equine Veterinary Journal article, authored by Cook RF, Cook SJ, Issel CJ, as a part of an infectious diseases monograph issue due out in 2009:

"Pathogenesis of Disease"

In animals infected with EIAV, there is a very close relationship between overt signs of disease and amounts of virus present (see Figure below).

Correlation between plasma-associated viral RNA burden and clinical signs of acute EIA. The rectal temperature (pink) and platelet level (blue) expressed as platelets per microliter of blood are shown in comparison with plasma-associated EIAV RNA burden (log10 /ml, solid bars)

Viral RNA burden and Clinical signs

Tissue associated viral burdens are at their highest levels during febrile episodes and decline several orders of magnitude concomitant with the resolution of clinical signs. It has been demonstrated that amounts of tissue-associated EIAV must reach a critical or threshold value in order to trigger disease (Cook et al. 2003). The observed variation in clinical signs may therefore be interpreted in the context of threshold viral burdens. Following acute infection, disease in normal, fully immunocompetent horses will only be produced if the inoculum strain of EIAV reaches or exceeds the threshold viral burden level before primary immune responses effectively limit viral replication. Therefore, to induce disease the infecting virus must possess sufficient replicative potential within its host. Although the spectrum of virulence among naturally occurring EIAV strains has not been rigorously determined it is known that any mutation in the viral genome that reduces viral replication rates in vivo will attenuate pathogenicity (Cook et al. 2003; Cook et al. 1998; Threadgill et al. 1993; Lichtenstein et al. 1995). In addition to viral replicative ability, differences between individual animals and between species of equid also play a significant role in the appearance of clinical signs following infection with EIAV. For example, in an experiment involving infection of horses/ponies with identical amounts of a pathogenic strain of EIAV derived from an infectious molecular clone it was observed some animals could control acute viral replication more efficiently and as a result had no obvious disease signs (Cook et al. 2003). Furthermore, a comparison between different species of equid infected with horse virulent EIAV strains showed that donkeys remained clinically unaffected and that their peak viral titers were at least a 1000-fold lower than in horses or ponies (Cook et al. 2001). A supplemental conclusion from research in different species is that once EIAV has been adapted to one equid host it may not replicate optimally in another species of equid.

Many of the clinical signs associated with acute EIA are caused by pro-inflammatory mediators released in response to tissue associated viral burdens reaching the threshold level and are not dependent on the development of viral-specific adaptive immune responses. This is demonstrated by the fact acute EIA signs occur in foals that lack mature T or B cells because of inherited Severe Combined Immunodeficiency (SCID) disease (Crawford et al. 1996; Tornquist et al. 1997) . The pathology of lentiviral-mediated disease is augmented by the fact that infection of macrophages by this group of viruses disrupts the regulation of host-cell gene expression to produce increases in the production of pro-inflammatory molecules such as tumor necrosis factor alpha (TNFα), interleukin 1 (IL-1α and IL-1β) and interleukin 6 (IL-6) (Yoo et al. 1996; Esser et al. 1996; Lechner et al. 1997; Lim et al. 2005; Swardson et al. 1997). This has been demonstrated in equine monocyte-derived macrophage cultures where infection with pathogenic strains of EIAV produces significant increases in the production of these cytokines (Lim et al. 2005) and during acute disease where significantly elevated blood levels of TNFα, IL-6 and transforming growth factorβ (TGFβ) have been observed (Tornquist et al. 1997; Sellon et al. 1999; Costa et al. 1997). IL-1, IL-6 and TNFα can induce febrile responses by activating the arachidonic pathway to increase production of prostaglandin E2 (PGE2). In addition to inducing febrile reactions, the cytokines released in response to EIAV infection may also cause thrombocytopenia. For example, TNFα and TGFβ have both been shown to suppress equine megakaryocyte colony growth (Tornquist and Crawford 1997) and in the mouse model injection with TNFα alone induces a profound thrombocytopenia by stimulating cells expressing the widely distributed 55 kDa Tumor Necrosis Factor Receptor 1 (TNFR1) to release platelet agonists such as thrombin, plasmin and serotonin (Tacchini-Cottier et al. 1998). Excessive TNFα production may also contribute to anemia in EIAV infected animals because it has the ability to suppress erythropoiesis (Felli et al. 2005; Zamai et al. 2000; Dufour et al. 2003; Moldawer et al. 1989). However, it is not the only mechanism because extensive phagocytosis of complement C3 coated erythrocytes also occurs in these animals, resulting in the presence of hemosiderin granules in the macrophages found in organs such as the liver, spleen and lymph nodes (Sentsui and Kono 1987; Perryman et al. 1971).

While clinical signs of acute EIA can be attributable to the storm of pro-inflammatory cytokines released in response to the burden of tissue-associated EIAV attaining the critical threshold level, adaptive immune responses, when present, also play a role in the pathogenesis of EIA. For example, platelets from EIAV infected horses have significant levels of bound IgG or IgM and so become destined for immune mediated destruction contributing to splenomegaly and hepatomegaly (Banks et al. 1972; Clabough et al. 1991). Furthermore, the glomeruli in the kidneys of chronically infected animals often show thickening of the glomerular tufts with both mesangial and epithelial cell proliferation. These diseased glomeruli have both immunoglobulin and complement C3 deposited at the basement membranes and mesangial areas (Henson and McGuire 1971).

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Updated on: February 17, 2010