Haemophilus influenzae increases the susceptibility and inflammatory response of airway epithelial cells to viral infections

Abstract

Nontypeable Haemophilus influenzae (NTHI), a common colonizer of lungs of patients with chronic obstructive pulmonary disease (COPD), can enhance expression of the cellular receptor intercellular adhesion molecule 1 (ICAM-1), which in turn can be used by major group human rhinoviruses (HRVs) for attachment. Here, we evaluated the effect of NTHI-induced up-regulation of ICAM-1 on viral replication and inflammatory responses toward different respiratory viruses. Therefore, human bronchial epithelial cells were pretreated with heat-inactivated NTHI (hi-NTHI) and subsequently infected with either HRV16 (major group), HRV1B (minor group), or respiratory syncytial virus (RSV). Pretreatment with hi-NTHI significantly up-regulated ICAM-1 in BEAS-2B cells and primary bronchial epithelial cells. Concomitantly, release of infectious HRV16 particles was increased in cells pretreated with hi-NTHI. Pretreatment with hi-NTHI also caused a significant increase in HRV16 RNA, whereas replication of HRV1B and RSV were increased to a far lesser extent and only at later time points. Interestingly, release of IL-6 and IL-8 after RSV, but not HRV, infection was synergistically increased in hi-NTHI-pretreated BEAS-2B cells. In summary, exposure to hi-NTHI significantly enhanced sensitivity toward HRV16 but not HRV1B or RSV, probably through ICAM-1 up-regulation. Furthermore, hi-NTHI pretreatment may enhance the inflammatory response to RSV infection, suggesting that preexisting bacterial infections might exaggerate inflammation during secondary viral infection.

Viral–bacterial interactions in the respiratory tract

“…Exposure of respiratory epithelial cells to H. influenzae increases the expression of ICAM-1, the main receptor for major group HRV. By doing so, the bacteria increase viral binding and replication of this type of virus in vitro (Gulraiz et al, 2015;Sajjan et al, 2006). Moreover, we have recently shown that H. influenzae and RSV can synergize in inducing the release of pro-inflammatory cytokines by respiratory epithelial cells (Bellinghausen et al, 2016).…”

Respiratory Syncytial Virus: Infection, Detection, and New Options for Prevention and Treatment

“…It has been shown in vitro or in vivo (using the cotton rat model) that treatment with S. pneumoniae prior to RSV challenge results in enhanced RSV replication (200). The increased RSV replication is also observed in vitro after pretreatment with heat-inactivated H. influenzae (201). Additionally, lipopolysaccharide (LPS; Gram-negative bacterial cell wall component) exposure results in a Th2 immune polarization and increased severity during subsequent RSV challenge (197).…”

The role of the local microbial ecosystem in respiratory health and disease

“…pathobiont presence enhancing viral acquisition and replication, might also occur: for example, H. influenzae has been shown to induce expression of ICAM-1 and TLR3-receptors, which enhanced rhinovirus binding and stimulated rhinovirus-induced chemokine production [147]. Furthermore, a recent in vitro study has shown that H. influenzae similarly increases viral replication of respiratory syncytial virus, which was related to the release of proinflammatory cytokines IL-6 and IL-8, suggesting specific bacterial community members can aggravate (inflammatory response to) viral infection [148]. Furthermore, pre-incubation of human bronchial epithelial cells with S. pneumoniae leads to increased susceptibility to infection with human metapneumovirus (figure 2d) [149].…”