Coinfection with Blood-Stage Plasmodium Promotes Systemic Type I Interferon Production during Pneumovirus Infection but Impairs Inflammation and Viral Control in the Lung

Chelsea L. Edwards, Vivian Zhang, Rhiannon B. Werder, Shannon E. Best, Ismail Sebina, Kylie R. James, Rebecca J. Faleiro, Fabian de Labastida Rivera, Fiona H. Amante, Christian R. Engwerda, Simon Phipps, Ashraful Haque

Acute Lower Respiratory Tract Infections (ALRTI) are the leading cause of global childhood mortality, with human Respiratory Syncytial Virus (hRSV) a major cause of viral ALRTI in young children worldwide. In sub-Saharan Africa, many young children experience severe illnesses due to hRSV or Plasmodium infection. Although malaria incidence in this region has reduced in recent years, there remains significant opportunity for co-infection. Recent data show that febrile young children infected with Plasmodium were often concurrently infected with respiratory viral pathogens, but were less likely to suffer pneumonia compared to non-Plasmodium infected children. Here, we hypothesized that blood-stage Plasmodium infection would modulate pulmonary inflammatory responses to a viral pathogen, but would not aid its control in the lung. To test this, we established a novel co-infection model: mice were simultaneously infected with pneumonia virus of mice (PVM; to model hRSV), and blood-stage P. chabaudi chabaudi AS (PcAS) parasites. We found that PcAS infection was unaffected by co-infection with PVM. In contrast, PVM-associated weight loss, pulmonary cytokine responses and immune cell recruitment to the airways was substantially reduced by co-infection with PcAS. Importantly, PcAS co-infection facilitated greater viral dissemination throughout the lung. Although Plasmodium-co-infection induced low levels of systemic IL-10, this regulatory cytokine played no role in modulating lung inflammation or viral dissemination. Instead, we found that Plasmodium co-infection drove an early systemic IFNβ response. Therefore, we propose that blood-stage Plasmodium co-infection may exacerbate viral dissemination and impair inflammation in the lung by dysregulating Type I IFN-dependent responses to respiratory viruses.