Both Influenza-Induced Neutrophil Dysfunction and Neutrophil-Independent Mechanisms Contribute to Increased Susceptibility to a SecondaryStreptococcus pneumoniaeInfection

Abstract

Since secondary Streptococcus pneumoniae infections greatly increase the mortality of influenza infections, we determined the relative roles of neutrophil-dependent and -independent mechanisms in increased susceptibility to S. pneumoniae during influenza infection. Mice infected with influenza for 6 days, but not 3 days, showed a significant increase in susceptibility to S. pneumoniae infection compared to mice not infected with influenza. There was significant neutrophil accumulation in the lungs of S. pneumoniae-infected mice regardless of whether or not they were infected with influenza for 3 or 6 days. Depletion of neutrophils in these mice resulted in increased susceptibility to S. pneumoniae in both the non-influenza-infected mice and mice infected with influenza for 3 days but not in the mice infected with influenza for 6 days, indicating that a prior influenza infection of 6 days may compromise neutrophil function, resulting in increased susceptibility to a S. pneumoniae infection. Neutrophils from the lungs of mice infected with influenza for 3 or 6 days exhibited functional impairment in the form of decreased phagocytosis and intracellular reactive oxygen species generation in response to S. pneumoniae. In addition, neutrophil-depleted mice infected with influenza for 6 days were more susceptible to S. pneumoniae than neutrophil-depleted mice not infected with influenza, indicating that neutrophil-independent mechanisms also contribute to influenza-induced increased susceptibility to S. pneumoniae. Pulmonary interleukin-10 levels were increased in coinfected mice infected with influenza for 6 days but not 3 days. Thus, an influenza infection of 6 days increases susceptibility to S. pneumoniae by both suppression of neutrophil function and by neutrophil-independent mechanisms such as enhanced cytokine production.

Neutrophils Ameliorate Lung Injury and the Development of Severe Disease during Influenza Infection

“…While the mouse serves as a convenient model to study factors that may modulate disease severity, previous attempts to elucidate the role of neutrophils have been limited by reliance on the use of mAb RB6-8C5 to deplete Ly6G high neutrophils in vivo (2,7,9,26). Herein, we demonstrate that mAb 1A8 can be used to identify and deplete Ly6G high neutrophils from mice during influenza virus infection.…”

“…Neutrophils play an important role in moderating bacterial load during respiratory viral infections (25,26), and secondary bacterial pneumonia is a common cause of death after influenza infection in humans. Therefore, it was important to ascertain bacterial counts in the lungs of virus-infected mice to ensure that severe disease observed in neutropenic animals was not due to overwhelming bacterial superinfection.…”

Aetiology of Acute Respiratory Infections in Children under Five Years in Nakuru, Kenya

“…Another mechanism of viral-bacterial interaction is viral predisposition and bacterial adherence in which explains that since attachment of a pathogen to mucosal surfaces is the first step towards respiratory disease, and viral infection alters the defense of the host epithelium in general, it has been postulated that viral presence may render the epithelium more susceptible to bacterial colonization [30]. Respiratory viruses may also directly affect the immune system, for example by impairment of neutrophil function, decreased oxidative burst and enhanced neutrophil apoptosis, thereby increasing susceptibility to bacterial super-infection [31]. Additionally, some strains of influenza virus infection may predispose to superinfection by S. aureus due to ineffective natural killer (NK) cell recruitment and activation [32].…”

Viral–bacterial interactions in the respiratory tract

“…Mouse models of secondary bacterial infections, however, point to a functional impairment of neutrophils rather than solely a lack of recruitment. Impaired bacterial clearance in influenza-or RSV-infected mice appeared to be related to decreased activity of the antimicrobial enzyme myeloperoxidase and decreased production of reactive oxygen species (LeVine et al, 2001;McNamee & Harmsen, 2006;Stark et al, 2006). Additionally, increased levels of IL-10, as observed during post-influenza pneumococcal pneumonia, are thought to negatively affect neutrophil function (van der Sluijs et al, 2004).…”