Immunopathogenesis of poxvirus infections: forecasting the impending storm

Abstract

Variola virus, the causative agent of smallpox, is a member of the poxvirus family and one of the most virulent human pathogens known. Although smallpox was eradicated almost 30 years ago, it is not understood why the mortality rates associated with the disease were high, why some patients recovered, and what constitutes an effective host response against infection. As variola virus infects only humans, our current understanding of poxvirus infections comes largely from historical clinical data from smallpox patients and from animal studies using closely related viruses such as ectromelia, myxoma and monkeypox. The outcome of an infection is determined by a complex interaction between the type of immune response mounted by the host and by evasion mechanisms that the virus has evolved to subvert it. Disease pathogenesis is also a function of both host and viral factors. Poxviruses are not only cytopathic, causing host tissue damage, but also encode an array of immunomodulatory molecules that affect the severity of disease. The ability of the host to control virus replication is therefore critical in limiting tissue damage. However, in addition to targeting virus, the immune response can inadvertently damage the host to such a degree that it causes illness and even death. There is growing evidence that many of the symptoms associated with serious poxvirus infections are a result of a 'cytokine storm' or sepsis and that this may be the underlying cause of pathology.

Animal Models of Orthopoxvirus Infection

“…104 This aspect of the disease is critical to explore because, in addition to the viral cytopathic effects, a cytokine storm is one of the proposed mechanisms of the pathogenesis and cause of death in human smallpox. 59,120 Inhalation of aerosolized viral particles is believed to be the route by which VARV and MPXV are naturally transmitted, and virus aerosolization is the means most likely to be used in a bioterrorism event. Thus, research utilizing aerosolized orthopoxviruses has been an important focus of animal model development, but there is value in exploring animal models using other routes of infection.…”

“…1 In fact, death in acute cases of mousepox is attributed to hepatic and splenic necrosis, presumably owing to the cytopathic effects of the virus. 120 Although hepatocellular degeneration was observed in human cases of smallpox, this did not appear to develop as a direct result of viral infection of the liver, and liver failure was not believed to be a cause of death, 53 as in mice infected with ECTV. An additional essential consideration in using this pathogen in research is the potential for spread of this virus through the research colony.…”

“…Because the disease was eradicated before modern molecular techniques were widely available, there remains much to learn about virus-host interactions, virulence factors, and the pathophysiology of this disease. 53,120 Seeding of other tissues, such as the liver, spleen, lymphoid tissues, and bone marrow, apparently occurred; however, VARV did not appear to replicate extensively enough to cause significant organ damage. 34 The only extensive viral cytopathic effects occurred in the skin and mucous membranes.…”

“…This is valuable not only because a low dose of virus causes lethal infections but also because so much is known about mouse genetics and immunology, providing a means for investigating immunomodulatory genes through targeted deletion. 33,120 A disadvantage of the mouse model of ectromelia infection is the hepatotropic nature of the virus in mice, a feature not observed in human infection with orthopoxviruses. 1 In fact, death in acute cases of mousepox is attributed to hepatic and splenic necrosis, presumably owing to the cytopathic effects of the virus.…”

Characterization of Macaque Pulmonary Fluid Proteome during Monkeypox Infection

“…Although both pathogenic MPXV and nonpathogenic VV infections produced increased levels of proteins indicative of inflammation, only MPXV infection produced a dramatic decrease of structural and metabolic proteins. It is generally believed that inflammation is the primary cause of mortality, contributing to fibrinonecrotic bronchopneumonia (19,57). In this study, the increased levels of inflammatory proteins occurred simultaneously with specific loss of structural and metabolic proteins, which suggests that inflammation may not be the direct or sole contributor to disease progression.…”