Synergism and Antagonism of Bacterial-Viral Coinfection in the Upper Respiratory Tract

mSphere. 2022 Feb 23;7(1):e0098421. doi: 10.1128/msphere.00984-21. Epub 2022 Jan 19.


Streptococcus pneumoniae (the pneumococcus) is a leading cause of pneumonia in children under 5 years of age. Coinfection by pneumococci and respiratory viruses enhances disease severity. Little is known about pneumococcal coinfections with respiratory syncytial virus (RSV). Here, we developed a novel infant mouse model of coinfection using pneumonia virus of mice (PVM), a murine analogue of RSV, to examine the dynamics of coinfection in the upper respiratory tract, an anatomical niche that is essential for host-to-host transmission and progression to disease. Coinfection increased damage to the nasal tissue and increased production of the chemokine CCL3. Nasopharyngeal pneumococcal density and shedding in nasal secretions were increased by coinfection. In contrast, coinfection reduced PVM loads in the nasopharynx, an effect that was independent of pneumococcal strain and the order of infection. We showed that this "antagonistic" effect was absent using either ethanol-killed pneumococci or a pneumococcal mutant deficient in capsule production and incapable of nasopharyngeal carriage. Colonization with a pneumococcal strain naturally unable to produce capsule also reduced viral loads. The pneumococcus-mediated reduction in PVM loads was caused by accelerated viral clearance from the nasopharynx. Although these synergistic and antagonistic effects occurred with both wild-type pneumococcal strains used in this study, the magnitude of the effects was strain dependent. Lastly, we showed that pneumococci can also antagonize influenza virus. Taken together, our study has uncovered multiple novel facets of bacterial-viral coinfection. Our findings have important public health implications, including for bacterial and viral vaccination strategies in young children. IMPORTANCE Respiratory bacterial-viral coinfections (such as pneumococci and influenza virus) are often synergistic, resulting in enhanced disease severity. Although colonization of the nasopharynx is the precursor to disease and transmission, little is known about bacterial-viral interactions that occur within this niche. In this study, we developed a novel mouse model to examine pneumococcal-viral interactions in the nasopharynx with pneumonia virus of mice (PVM) and influenza. We found that PVM infection benefits pneumococci by increasing their numbers in the nasopharynx and shedding of these bacteria in respiratory secretions. In contrast, we discovered that pneumococci decrease PVM numbers by accelerating viral clearance. We also report a similar effect of pneumococci on influenza. By showing that coinfections lead to both synergistic and antagonistic outcomes, our findings challenge the existing dogma in the field. Our work has important applications and implications for bacterial and viral vaccines that target these microbes.

Keywords: Streptococcus pneumoniae; coinfection; influenza; murine pneumonia virus; pneumococcus; pneumonia virus of mice; respiratory syncytial virus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Animals
  • Antibiosis*
  • Coinfection / immunology
  • Coinfection / microbiology*
  • Coinfection / virology*
  • Cytokines / analysis
  • Cytokines / immunology
  • Disease Models, Animal
  • Influenza A virus / genetics
  • Influenza A virus / immunology
  • Mice
  • Mice, Inbred C57BL
  • Murine pneumonia virus / genetics
  • Murine pneumonia virus / immunology
  • Nasopharynx / virology
  • Orthomyxoviridae Infections / immunology
  • Orthomyxoviridae Infections / virology
  • Pneumococcal Infections / virology*
  • Pneumovirus Infections / immunology
  • Pneumovirus Infections / virology*
  • Respiratory System / immunology
  • Respiratory System / virology*
  • Streptococcus pneumoniae / genetics
  • Streptococcus pneumoniae / immunology
  • Viral Load


  • Cytokines