Innate Immunity to Mouse Cytomegalovirus

Abstract

Innate immunity, the first line of defense against pathogens, plays an essential role in the initial phase of viral infection, before expansion, clonal selection, and differentiation of antigen-specific Tand B-cells occur. The innate immune system comprises cellular and humoral components. Among cellular components, major players in the innate immune response are macrophages, dendritic cells (DCs), and natural killer (NK) cells ( 1 ). Macrophages express an enormous phagocytic capacity, which makes them important for the clearance of infected cells as well as for the initiation of the innate immune response ( 2 ). DCs, major antigen presenting cells, are essential for the activation of NK cells as well as for Tand B-lymphocytes that lead to the final clearance of viral antigens ( 3 ). The rapid activation of NK cells and their recruitment to the sites of infection define their central position in the innate immunity. The antiviral functions of NK cells are mediated either through direct lysis of infected cells or the secretion of antiviral cytokines like IFN-γ and TNF-α ( 4 ). NK cells also play a role in the regulation of specific immune response thus linking innate and adaptive immunity ( 5 ). The cytomegaloviruses (CMVs) are members of the β-herpesvirinae subfamily of the herpesviridae. Primary human CMV (HCMV) infection usually passes asymptomatically due to the effective host’s immune response. Yet, in spite of the fully primed immune response, the virus is able to establish a lifelong latency from which the reactivation may occur whenever the immune response is compromised. In contrast to immunocompetent hosts, HCMV infection of immunodeficient individuals may induce severe illness and high mortality ( 6 ). Moreover, one of the most common viral congenital infections in humans is caused by HCMV, frequently resulting in developmental abnormalities of the central nervous system and severe neurological impairments ( 6 , 7 ). The species specificity of HCMV precludes the studies of the pathogenesis of HCMV infection in animal hosts. Therefore, animal CMVs, particularly mouse CMV (MCMV), have been the most commonly used models to study the CMV infection and pathogenesis ( 8 ). Cellular immunity is indispensable for the control of primary MCMV infection and for the establishment and maintenance of latency ( 9 ), whereas specific antibodies prevent the spread of the virus after reactivation ( 10 ). During the co-evolution with their hosts CMVs have developed multiple strategies to compromise or evade the immune response ( 11 ). However, as pointed above, mechanisms of innate and acquired immunity can overcome these viral immunomodulations and successfully control the infection. This game of hide-and-seek prompts further research, which could lead to a better understanding of the importance of NK cells and other components of innate immunity to CMV infection as well as the role of viral immunoevasins in their modulation.