CD8⁺ lymphocytes but not B lymphocytes are required for protection against chronic hepatitis E virus infection in chickens

Abstract

Hepatitis E is an important global disease, causing outbreaks of acute hepatitis in many developing countries and sporadic cases in industrialized countries. Hepatitis E virus (HEV) infection typically causes self-limiting acute hepatitis but can also progress to chronic disease in immunocompromised individuals. The immune response necessary for the prevention of chronic infection is T cell-dependent; however, the arm of cellular immunity responsible for this protection is not currently known. To investigate the contribution of humoral immunity in control of HEV infection and prevention of chronicity, we experimentally infected 20 wild-type (WT) and 18 immunoglobulin knockout (JH-KO) chickens with a chicken strain of HEV (avian HEV). Four weeks postinfection (wpi) with avian HEV, JH-KO chickens were unable to elicit anti-HEV antibody but had statistically significantly lower liver lesion scores than the WT chickens. At 16 wpi, viral RNA in fecal material and liver, and severe liver lesions were undetectable in both groups. To determine the role of cytotoxic lymphocytes in the prevention of chronicity, we infected 20 WT and 20 cyclosporine and CD8 + antibody-treated chickens with the same strain of avian HEV. The CD8 + lymphocyte-depleted, HEV-infected chickens had higher incidences of prolonged fecal viral shedding and statistically significantly higher liver lesion scores than the untreated, HEV-infected birds at 16 wpi. The results indicate that CD8 + lymphocytes are required for viral clearance and reduction of liver lesions in HEV infection while antibodies are not necessary for viral clearance but may contribute to the development of liver lesions in acute HEV infection. K E Y W O R D S avian HEV, CD8 + lymphocytes, chronic infection, hepatitis E virus How to cite this article: Rogers E, Todd SM, Pierson FW, et al. CD8 + lymphocytes but not B lymphocytes are required for protection against chronic hepatitis E virus infection in chickens.

Mechanisms of CD8+ T-cell failure in chronic hepatitis E virus infection

“…These observations in the human setting are in agreement with recent data from the chicken as well as rhesus macaque HEV infection models that indicated an important role of HEV-specific CD8+ T cells in viral clearance. 3,4 The number of HEV-specific T-cell responses correlated negatively with viral load as well as ALT levels in chronic HEV infection (Fig. S4C,D).…”

“…Recent in vivo evidence from 2 animal models (chicken and rhesus macaque) demonstrates an important role of HEV-specific CD8+ T cells in HEV control. 3,4 However, in humans, there is still a paucity of data on HEV-specific CD8+ T-cell immunity. 5 Studies using recombinant HEV capsid protein (corresponding to open reading frame [ORF] 2) as well as overlapping peptides covering some or all HEV domains (ORF1-3) showed broad and vigorous HEV-specific CD8+ T-cell responses in immunocompetent patients with acute infection that contracted upon resolution of infection.…”

The pivotal role of CD8+ T cells in hepatitis E virus infection

“…9 Although recent studies suggested HEV clearance depends on an effective virus-specific CD8+ T-cell response, there is a remarkable deficit in knowledge about the contribution of adaptive T-cell immunity to the control and pathogenesis of HEV infection. 10,11 In particular, little information is currently available about the abundance, phenotype, functional capacity and fate of pre-existing and induced HEV-specific CD8+ T cells, which might determine the divergent outcomes of infection.…”