Hantavirus infection pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Hantaviruses belong to the bunyavirus family of viruses. There are 5 genera within the family: bunyavirus, phlebovirus, nairovirus, tospovirus, and hantavirus. Each is made up of negative-sensed, single-stranded RNA viruses. All these genera include arthropod-borne viruses, with the exception of hantavirus, which is rodent-borne. Each Hantavirus species is associated with a specific rodent in a given geographic region. Hantavirus is usually transmitted via the inhalation of aerosolized viral antigens or rodent bites

Pathophysiology

Reservoir

Each Hantavirus species is associated with a specific rodent in a given geographic region. Rodent subfamilies associated with hantaviruses include

• Arvicolinae (Europe)
• Murinae (Europe and Asia)
• Sigmodontinae (Americas)

Transmission

Hantavirus is usually transmitted via the inhalation of aerosolized viral antigens or rodent bites. Human to human transmission is seen in American Hantaviruses species (Andes virus).

Incubation period

The incubation period of hantavirus infection is of 9 to 33 days.

Seeding

• Following inhalation the virus replicates in pulmonary macrophages and dendritic cells.

Pahtogenesis

The pathogenesis of hantavirus infection can be described by 1)impairment of the barrier function of endothelial cells 2) fluid extravasation and 3) subsequent organ failure.

Impairment of the barrier function of endothelial cells

• The primary target cells of hantavirus infection are endothelial cells of capillaries.
• Hantaviruses attach to beta-3 integrin receptors of endothelial cells and stimulate T cells.
• Neutralizing antibody (NAbs) are produced as a result of stimulation and beta-3 integrins are inactivated.
• Inactivation of virus-bound beta-3-integrins contributes to deregulation of vascular endothelial growth factor receptor-2 (VEGFR2) and diminished antagonism of vascular endothelial growth factor (VEGFA)
• This leads to impairment of vascular endothelial (VE) cadherin expression and subsequent loss of endothelial barrier function.
• Platelets are consumed in high number in response to the damage to the endothelial layer resulting in thrombocytopenia.

Fluid extravasation

• Neutralizing antibody (NAbs) also inhibit innate type I interferon (IFN) responses of endothelial cells.
• This results in inhibition of upregulation of CD73 by IFN-beta on endothelial cells and promotes vascular leakage.

Mutliorgan failure

• Hantaviruses demonstrated to have an immunoreceptor tyrosine-based activation motif (ITAM) on their G1 envelope glycoproteins.
• Immunoreceptor tyrosine-based activation motif along with local T-cell cytokine production results in cellular downstream and immune cell dysfunction.
• Attachment of hantvirus to beta-2 integrin receptors on neutrophils also induces the release of neutrophil extracellular traps.
• Sensitized mononuclear cells infiltrate the lung, myocardial interstitium, and spleen to produce cytokines, particularly TNF-alpha and interferon-gamma, resulting in pulmonary edema and myocarditis