Human Metapneumovirus Elicits Weak IFN-γ Memory Responses Compared with Respiratory Syncytial Virus

Abstract

Human metapneumovirus (MPV) is a recently discovered pathogen that causes repeated lower respiratory tract infections beginning in infancy. The prevalence, nature and control of human regulatory responses to MPV are unknown. In this study, we develop and optimize systems to evaluate MPV-driven cytokine responses. Using primary culture of human PBMC from previously exposed adults, MPV-stimulated responses were directly compared with those elicited by genetically and clinically similar respiratory syncytial virus (RSV). Intense IL-6 production was evident following culture with infectious or inactivated RSV. MPV elicited IL-6 responses averaging 3.5-fold more intense (p < 0.001). Virus-dependent expression of IL-11, IL-12, IFN-α, and other innate immunity cytokines differed little between MPV and RSV. When examining adaptive immunity, RSV infection elicited strong IFN-γ responses by all 60 adults. In marked contrast, MPV elicited IFN-γ in a lower frequency of adults (p < 0.002) and at levels averaging 6-fold weaker (p < 0.001). These Th1-dominated responses were CD4, CD8, CD86 dependent, and were closely paralleled by strong virus-driven IL-10 and CCL5 production. For MPV and RSV, Th2 (IL-5, IL-13) responses were sporadic, occurring in 10–40% of the population. Thus, MPV and RSV, although both ubiquitous and leading to very high levels of infection, seroconversion, and clinically similar presentation in the population, evoke distinct innate and adaptive T cell-dependent cytokine responses. Although both viruses yield Th1-dominated responses with strong IL-10 and CCL5 production, MPV restimulation results in markedly more robust IL-6 and significantly weaker adaptive cytokine responses, in both prevalence and intensity, than does RSV.

Aberrant T cell immunity triggered by human Respiratory Syncytial Virus and human Metapneumovirus infection

“…142 However, PBMCs, from healthy adults, stimulated with heat-inactivated hMPV promotes the induction of high levels IL-6 (a T H 2 polarizing cytokine that prevents T H 1 differentiation 143 ) and low levels of IFN-g and CCR5 (T H 1 cytokines) when compare with hRSV-stimulated PBMCs, thus suggesting a polarization toward a T H 2 response. 144 In contrast, other studies demonstrate that infants undergoing hMPV infection presented lower levels of pro-inflammatory cytokines compare with infants undergoing hRSV or influenza infection, including TNF-a and IL-1b, two cytokines related to the chemotaxis of neutrophils in lungs, as well as IL-12, IL-6 and IL-8. 145 Furthermore, in infants undergoing hMPV infection it was observed that a predominant T H 1 response is generated, since it was detected an increase in the IFN-g/ IL-4 ratio in nasal airway secretions.…”

“…26 This impairment may contribute to a delayed T H 1 response. Indeed, CD4 C T cells elicit a poor IFN-g response when activated with hMPV-infected human peripheral blood mononuclear cells in vitro, 144 suggesting that these hMPV-infected cells can also inhibit the function of CD4 C T cells to stimulate an efficient antiviral T H 1 immune response in humans. The impairment of T cell immunity could be the result of impaired DC functions by hMPV, possibly through of a soluble factor derived from hMPV-infected DCs, as supernatants from these infected cells impairs T cells activation when stimulated by plate-bound antiCD3e and anti-CD28.…”

Human Metapneumovirus and Human Bocavirus in Children

“…When specifically compared with RSV infection, however, the cytokine profile of hMPV is unique in some aspects. First, lower levels of TH 1 cytokines (particularly interferon-␥, tumor necrosis factor-␣, and macrophage inflammatory protein 1␣) are observed compared with RSV infections (20,23,24). Changes in IL-6, however, have been variably reported, with both higher (23) and lower (24) levels being reported after hMPV infections in humans.…”

Human metapneumovirus keeps dendritic cells from priming antigen‐specific naive T cells

“…We evaluated whether immature mouse DCs are permissive to hMPV infection by inoculating DCs with variable amounts of infectious (MOI [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] and UV-inactivated hMPV (UV-hMPV). After inoculation, DCs expressing the fusion and nucleoprotein of hMPV could be easily identified by fluorescence microscopy among other noninfected DCs (Fig.…”

“…6,7 These findings suggest that hMPV may have evolved molecular mechanisms to evade host immunity and prevent immune clearance. [8][9][10][11][12] Dendritic cells (DCs) are professional antigen-presenting cells with the unique capacity to activate naive T cells, which later will exert an anti-viral immune response. [13][14][15] Priming of T cells requires DCs to efficiently capture and present viral proteins as antigenic peptide-MHC complexes and to provide co-stimulatory signals needed for full T-cell activation.…”