Table 6.

Summary of CCHFV immunobiology: knowns and unknowns

Process/response	Known	Unknown
Infection	• Occurs via tick bite or mucosal exposure.	• How does route of infection affect host response?
Tick-borne exposure	• Tick-derived salivary factors are delivered along with CCHFV particles. • Resident tissue cells and surveilling immune cells are the likely initial targets of CCHFV replication. • Surveilling immune cells detect virus and traffic back to lymphoid tissue to initiate innate and adaptive immune responses.	• Is initial amplification at the site of the tick bite required or can virus directly enter blood circulation to seed distant tissues? • Role of tick salivary factors in modulating the innate response to infection. • Role of resident tissue cells in initial viral amplification. • Role of leukocyte trafficking in spread of CCHFV to lymphoid tissues.
Cellular infection	• CCHFV inhibits RIG-I mediated sensing. • CCHFV L-protein OTU-like domain blocks ISG15 labeling of host and viral proteins. • The host MXA protein interacts with CCHFV NP to inhibit viral replication. • Established CCHFV infections are resistant to type I IFN-mediated restriction. • Virus infection elicits a pro-inflammatory cytokine response. • NSs protein can depolarize mitochondria and activate intrinsic apoptosis pathways. • NP has anti-apoptotic activity, blocking both intrinsic and extrinsic apoptosis pathways, and a highly conserved DEVD-cleavage motif that can be cleaved by host caspases.	• Other CCHFV antagonists of innate immunity. • Other host proteins are likely involved in the restriction of CCHFV. • Relative role of cytoplasmic and endosomal sensors. • Why is CCHFV resistant to type-I IFN once infection is established? • Can established CCHFV infections block signaling from the type I IFN receptor? • Why does CCHFV possess proteins with pro- and anti-apoptotic function and retain a sequence that targets the CCHFV NP for cleavage by host caspases? • Does blockade of apoptosis by CCHFV result in inflammatory cell death such as necrosis or necroptosis?
Liver pathology	• Virus infection causes liver pathology characterized by hepatocellular necrosis. • Infected innate immunity cells produce inflammatory cytokines. • Pro-inflammatory cytokines drive recruitment of further inflammatory cells, leading to further tissue damage. • Macrophages and dendritic cells likely serve as key antigen-presenting cells for initiation of adaptive immunity. • CCHFV infection of innate cells causes partial activation, potentially impairing resulting stimulation of adaptive immune cells.	• What causes tissue pathology? Direct viral killing of infected cells, killing of infected cells by adaptive immune responses (CTLs or antibody-dependent cellular cytotoxicity), and/or recruitment of inflammatory cells to infected tissues? • Does virus cause inflammatory immune signaling in infected innate cells? • How does CCHFV infection leads to incomplete activation of APCs? • What role do reactive oxygen species play in tissue damage? • What cell types are required for type I IFN response in vivo? Where does the initial type I IFN, crucial for surviving CCHFV, come from?
Adaptive immunity	• Deficiencies in B- and T-cell responses can lead to rapidly fatal infections in mouse models. • Both B- and T-cells likely contribute to survival in acute CCHF. • Neutralization of infectious virus may be dispensable for virus control.	• Effector functions required of B- and T-cells for protection? • Is virus neutralization truly dispensable for protection? • Role of Fc-dependent effector functions, such as activation of complement or ADCC. • Are CD4 T-helper cells required for effective antibody and CD8 T-cell functions? • Are CD4 T-cells required for antiviral cytokine production? • Role of CD8 T-cells in infection control? Crucial for cell lysis or cytokine production? • Can CCHFV block granzyme-mediated cell killing by CTLs and NK cells?