Cell-Mediated Responses to Human Metapneumovirus Infection

Abstract

Viruses are the most common cause of acute respiratory tract infections (ARTI). Human metapneumovirus (hMPV) frequently causes viral pneumonia which can become life-threatening if the virus spreads to the lungs. Even though hMPV was only isolated in 2001, this negative-stranded RNA virus has probably been circulating in the human population for many decades. Interestingly, almost all adults have serologic evidence of hMPV infection. A well-established host immune response is evoked when hMPV infection occurs. However, the virus has evolved to circumvent and even exploit the host immune response. Further, infection with hMPV induces a weak memory response, and re-infections during life are common. In this review, we provide a comprehensive overview of the different cell types involved in the immune response in order to better understand the immunopathology induced by hMPV. Such knowledge may contribute to the development of vaccines and therapeutics directed against hMPV.

Keywords: evasion strategies; human metapneumovirus; innate and adaptive immune response.

Figure 1

Human metapneumovirus (hMPV) virion structure with viral proteins and their function. Schematic representation of the hMPV viral particle (A) and viral genome with encoded proteins (B): nucleoprotein (N), phosphoprotein (P), matrix protein (M), fusion protein (F), matrix-2 proteins (M2-1 and M2-2), small hydrophobic (SH) protein, glycoprotein (G), and large (L) polymerase protein.

Figure 2

Schematic overview of the interplay between different cell types leading to pulmonary immunopathology upon hMPV infection described in this review. Briefly, dendritic cells (DC), airway epithelial cells (AECs) and alveolar macrophages (AMφ) are the major cell populations that sense hMPV infections. AMφ initiate the primary innate immune response and viral clearance by phagocytosis of hMPV virions. Infected AECs release several pro-inflammatory cytokines, chemokines, and interferons (IFNs) and eventually undergo apoptosis. The signaling pathways induced upon hMPV infection are presented in the zoomed-in box on the right. Activated DCs can stay in the lung and promote local immune responses or they can migrate to the draining lymph nodes and prime naïve T cells (Th0). The activated effector CD4+ and CD8+ T cells expand and migrate back to the lung. Th0 cells can differentiate into several T cell subsets upon hMPV infection including Th1, Th2, regulatory T cells (Tregs), NKT cells, and cytotoxic lymphocytes (CTLs). The last two subsets are able to kill infected cells by the release of cytotoxic granules. Chemokine release by infected AECs recruits several other inflammatory cell types such as NK cells, monocytes, and neutrophils, mediating viral clearance via various killing mechanisms. Another important step in the control of viral infection later in the infection is humoral response through the production of virus-specific antibodies by B cells.