Insights into the Pathogenesis of Viral Haemorrhagic Fever Based on Virus Tropism and Tissue Lesions of Natural Rift Valley Fever

Abstract

Rift Valley fever phlebovirus (RVFV) infects humans and a wide range of ungulates and historically has caused devastating epidemics in Africa and the Arabian Peninsula. Lesions of naturally infected cases of Rift Valley fever (RVF) have only been described in detail in sheep with a few reports concerning cattle and humans. The most frequently observed lesion in both ruminants and humans is randomly distributed necrosis, particularly in the liver. Lesions supportive of vascular endothelial injury are also present and include mild hydropericardium, hydrothorax and ascites; marked pulmonary congestion and oedema; lymph node congestion and oedema; and haemorrhages in many tissues. Although a complete understanding of RVF pathogenesis is still lacking, antigen-presenting cells in the skin are likely the early targets of the virus. Following suppression of type I IFN production and necrosis of dermal cells, RVFV spreads systemically, resulting in infection and necrosis of other cells in a variety of organs. Failure of both the innate and adaptive immune responses to control infection is exacerbated by apoptosis of lymphocytes. An excessive pro-inflammatory cytokine and chemokine response leads to microcirculatory dysfunction. Additionally, impairment of the coagulation system results in widespread haemorrhages. Fatal outcomes result from multiorgan failure, oedema in many organs (including the lungs and brain), hypotension, and circulatory shock. Here, we summarize current understanding of RVF cellular tropism as informed by lesions caused by natural infections. We specifically examine how extant knowledge informs current understanding regarding pathogenesis of the haemorrhagic fever form of RVF, identifying opportunities for future research.

How Viruses Use the VCP/p97 ATPase Molecular Machine

“…RVFV is a member of the Bunyaviridae family, which have negative-sense, single-stranded, segmented RNA genomes [ 111 ]. This virus causes Rift Valley fever (RVF) in humans and livestock [ 112 ]. Although RVFV is mostly associated with limited febrile illness in humans, some individuals may experience hemorrhagic fever, neurological disorders, liver failure, blindness, or, rarely, death [ 113 ].…”

Transboundary Animal Diseases, an Overview of 17 Diseases with Potential for Global Spread and Serious Consequences

“…Direct contact with fluids or tissues from infected animals, or with contaminated fomites, pose a risk of infection for susceptible animals [541]. Sheep and cattle are the primary livestock species of concern, leading to the majority of virus spread and the majority of clinical disease [541,543,544]. However, goats, camelids, nonhuman primates, cats, dogs, and horses are also susceptible, sometimes without signs of clinical disease.…”

“…Common clinical signs of RVF include abortions in female adult animals, fever, swollen lymph nodes, and lack of appetite. Weakness, nasal discharge, and bloody diarrhea are also prominent features in infected sheep [541,543,544]. Cattle tend to exhibit hypersalivation, diarrhea, and decreased milk production.…”

“…Consequently, RVF can result in significant losses to production and food supply, along with high mortality, in infected livestock [3]. Young animals exhibit different disease progression and appear to more susceptible, though more research is needed to better understand the mechanisms involved in the differences between young and older animals [541,544].…”

How Viruses Use the VCP/p97 ATPase Molecular Machine

“…RVFV is a member of the Bunyaviridae family, which have negative-sense, single-stranded, segmented RNA genomes [108]. This virus causes Rift Valley fever (RVF) in humans and livestock [109]. Although RVFV is mostly associated with limited febrile illness in humans, some individuals may experience hemorrhagic fever, neurological disorders, liver failure, blindness, or, rarely, death [110].…”