Differential Production of Inflammatory Cytokines in Primary Infection with Human Metapneumovirus and with Other Common Respiratory Viruses of Infancy

Abstract

Viral respiratory infections are the most frequent cause of hospital admission for infants and young children during winter. However, the mechanisms of illness that are associated with viral lower-respiratory-tract infection (LRI) are unclear. A widely accepted hypothesis attributes the pathogenesis of viral LRI in infants to the induction of innate inflammatory responses. This theory is supported by studies showing that Toll-like receptor 4 is activated by respiratory syncytial virus (RSV), leading to production of inflammatory cytokines. We prospectively examined previously naive infants in Buenos Aires, Argentina, who had either upper- or lower-respiratory-tract symptoms. Infection with human metapneumovirus (hMPV) was second only to RSV in frequency. Both viruses were associated with rhinorrhea, cough, and wheezing; however, hMPV elicited significantly lower levels of respiratory inflammatory cytokines than did RSV. Symptoms in infants infected with influenza virus were different from those in infants infected with RSV, but cytokine responses were similar. These findings suggest that hMPV and RSV either cause disease via different mechanisms or share a common mechanism that is distinct from innate immune activation.

Animal models for human Metapneumovirus (HMPV) infections

“…Later during the infection, a Th2-type IL10 expression and a delayed CTL activity evolved that coincided with persistent virus replication in the lungs of infected animals. These findings are congruent with the earlier finding by Laham et al [11], who observed an attenuated inflammatory response in infected children. In their interesting study on the persistence of HMPV in mice, Hamelin et al [7] found that the persisting viral HMPV RNA was accompanied by a significant ongoing pulmonary inflammation until day 154 post infection, whereas the elevated secretion of mucus was observed only until day 12.…”

“…The findings showing that depletion of T cells or NK cells in infected BALB/c mice result in increased virus titers in the lungs are consistent with this hypothesis [1]. These latter data describing the inflammatory response in HMPV-infected mice [2] are consistent with the findings of a recent prospective study that demonstrated much lower levels of respiratory inflammatory cytokines in HMPV-infected infants than in those infected with RSV [11]. The authors suggested that HMPV and RSV either cause disease via different mechanisms or share a common mechanism that is distinct from innate immune activation.…”

“…In contrast to RSV, HMPV elicited a significantly lower inflammatory cytokine response [11]. This may indicate that the mechanisms of pathogenesis are different for both viruses.…”

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

“…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. Taken together, this data indicate that hMPV induces a complex immune response, which might include a mixed T H 1/T H 2 response, similar to what was observed in mice, though further studies are required to evaluate the T cell response in humans upon hMPV infection.…”

Elevated Serum Levels of Thymic Stromal Lymphopoietin in Wheezing Children Infected with Human Metapneumovirus

“…hMPV infection of airway epithelial cells is cytopathic, and the resultant cell injury triggers a series of inflammatory reactions. On the other hand, an unbalanced T helper (Th)1/Th2 immune response to hMPV infection may occur, which would release a series of inflammatory mediators, cytokines, and chemokines, and cause wheezing (21)(22)(23). Studies have shown that TSLP, a newly discovered cytokine, may aggravate excessive The differences between 2 groups were compared using the nonparametric Mann-Whitney 2-sample U test for unpaired data.…”