Expansion of myeloid suppressor cells and suppression of Lassa virus-specific T cells during fatal Lassa fever.

Abstract

Lassa fever is a highly lethal hemorrhagic fever endemic to West Africa. In the absence of efficient prophylactic or therapeutic countermeasures, it poses a substantial threat to public health in this region. The pathophysiological mechanisms underlying the severity of the disease are poorly known because Lassa virus (LASV), its causative agent, has to be handled in BSL-4 laboratories and access to clinical samples is difficult. The control of Lassa fever is associated with a rapid and well-balanced immune response and viral clearance. However, severe disease is characterized by uncontrolled innate immune activation and symptoms reminiscent of sepsis and a cytokine storm. In a model of cynomolgus monkeys infected with two different strains of the virus, one causing moderate disease and the other a lethal outcome, we show that the control of LASV infection is characterized by the induction of a LASV-specific T-cell response, whereas severity is associated with the expansion of suppressive myeloid cells, alterations of the stromal network of secondary lymphoid organs, and the anergy of specific T cells. These results suggest that T cells are crucial for the control of LASV and that immunomodulatory therapeutics, such as checkpoint inhibitors, could contribute to new therapeutic strategies to treat Lassa fever. They also highlight how immunosuppressive mechanisms described in sepsis and cancer patients may play a role in the pathogenicity of Lassa fever, as well as in other similar hemorrhagic fevers.