Measles virus-induced suppression of immune responses

Abstract

Measles is an important cause of child mortality that has a seemingly paradoxical interaction with the immune system. In most individuals, the immune response is successful in eventually clearing measles virus (MV) infection and in establishing life-long immunity. However, infection is also associated with persistence of viral RNA and several weeks of immune suppression, including loss of delayed type hypersensitivity responses and increased susceptibility to secondary infections. The initial T-cell response includes CD8+ and T-helper 1 CD4+ T cells important for control of infectious virus. As viral RNA persists, there is a shift to a T-helper 2 CD4+ T-cell response that likely promotes B-cell maturation and durable antibody responses but may suppress macrophage activation and T-helper 1 responses to new infections. Suppression of mitogen-induced lymphocyte proliferation can be induced by lymphocyte infection with MV or by lymphocyte exposure to a complex of the hemagglutinin and fusion surface glycoproteins without infection. Dendritic cells (DCs) are susceptible to infection and can transmit infection to lymphocytes. MV-infected DCs are unable to stimulate a mixed lymphocyte reaction and can induce lymphocyte unresponsiveness through expression of MV glycoproteins. Thus, multiple factors may contribute both to measles-induced immune suppression and to the establishment of durable protective immunity.

Fig. 1. Schematic diagram outlining an overview of the pathogenesis of measles from the time of virus infection through recovery

(A) Virus infection is initiated in the respiratory tract and then spread systemically to infect multiple organs including lymphoid tissue, liver, lungs, and skin. The types of cells infected include epithelial cells, endothelial cells, B and T lymphocytes, monocytes/macrophages, and dendritic cells. Virus clearance begins with the onset of the rash. Clearance of infectious virus is complete 20 days after infection, but viral RNA (represented by the dashed line) persists at multiple sites. (B) Clinical signs and symptoms begin approximately 10 days after infection with prodromal symptoms of fever, conjunctivitis, and appearance of Koplik’s spots followed by the maculopapular rash that lasts 3–5 days. (C) The rash is a manifestation of the adaptive immune response with infiltration of CD4⁺ and CD8⁺ T cells into sites of virus replication and initiation of virus clearance. There is a rapid activation, expansion, and then contraction of virus-specific CD8⁺ T cells. The CD4⁺ T-cell response appears at the same time, but activation is prolonged. MV-specific IgM appears with the rash and is commonly used to confirm the diagnosis of measles. This is followed by the sustained synthesis of MV-specific IgG. Immune suppression is evident during acute disease and for many weeks after recovery. (D) Cytokines and chemokines that are produced during infection in sufficient quantities to be found in plasma in elevated amounts are of several distinct types. Early, the chemokine IL-8 is increased. During the rash, IFN-γ and IL-2 are produced by activated type 1 CD4⁺ T cells and by CD8⁺ T cells. After resolution of the rash, type 2 and regulatory CD4⁺ T cells produce IL-4, IL-10, and IL-13.

Fig. 2. Manifestations of immune suppression during measles

(A) Delayed type hypersensitivity skin test responses to tuberculin in Peruvian children before (control) and after the onset of measles (139). (B) Proliferation in response to stimulation with phytohemagglutinin of PBMCs from rhesus macaques during a primate center outbreak of measles (66).