Study: Time-Dependent Increase in Susceptibility and Severity of Secondary Bacterial Infection during SARS-CoV-2 Infection. Image Credit: Maxx-Studio/Shutterstock
Previous studies have shown that bacterial pathogens, such as Mycoplasma pneumoniae, Chlamydophila pneumoniae, Klebsiella pneumoniae, Legionella pneumophila, Pseudomonas aeruginosa, Acinetobacter baumanii, Staphylococcus aureus, etc., cause secondary infections with other viruses, e.g., influenza A virus (IAV).
Recently, researchers detected Pneumococcus from the throat swabs of hospitalized COVID-19 patients who did not require intensive care unit (ICU) admission or ventilator support. The use of face masks, as a non-pharmaceutical measure, has significantly reduced bacterial transmission. Scientists stated the importance of understanding whether SARS-CoV-2 infection predisposes individuals to bacterial infections.
Prior studies have indicated that the impact of secondary infection by bacterial pathogens appeared to be lower during the COVID-19 pandemic. However, this condition can change over the years with the emergence of new variants.
Scientists revealed that neutrophils and macrophages, which clear bacteria during viral-bacterial coinfection, have been reported to be dysregulated during SARS-CoV-2 infection.
A prior study used animal models to investigate the viral and immune dynamics in the lower respiratory tract. It reported that bacteria could enhance the pathogenicity of coronaviruses. Several studies associated with influenza-bacterial coinfection revealed that vulnerability and pathogenicity of bacterial coinfections are time-dependent, with the greatest mortality observed when bacterial infection occurs at seven days post-virus infection (pvi).
During influenza, the gradual increase in susceptibility to bacterial coinfection occurred predominantly due to reduction or dysfunction of resident alveolar macrophages (AMΦ). Bacterial infection remained dynamic throughout IAV infection and maximal at seven days pvi.
Prior in vitro studies have shown that AMΦs become productively infected with SARS-CoV-2, which initiates altered cytokine production and responsiveness. Additionally, during SARS-CoV-2 infection, myeloid dysfunction, delayed IFN responses, and CD8+ T cell depletion have been reported. Researchers have stated that more studies are required to understand the possibility of bacterial coinfection and how this would impact the immune cells, viral, and pathological dynamics.
A new study
A new study published on the bioRxiv* preprint server has evaluated bacterial susceptibility during SARS-CoV-2 infection. It further determined if a synergy exists between SARS-CoV-2 and pneumococcus. In this study, researchers triggered mild to moderate SARS-CoV-2 infection in K18-hACE2 mice and, subsequently, coinfected them 3, 5, or 7 days later with pneumococcus. Scientists reported that bacteria failed to establish infection at three days pvi.
However, coinfection occurred at 5 and 7 days pvi, with increased lethality in a sex-independent manner. This time-dependency is similar to that of influenza-bacterial coinfections; however, the lethality during the SARS-CoV-2-pneumococcal coinfection was found to be delayed.
Researchers reported that viral dynamics and lung pathology remained unchanged within the first 24 hours of coinfection. A decrease in immune cells and pro-inflammatory cytokines was observed in the coinfected animals' lungs at five days pvi but not at seven days pvi.
The authors stated that more studies are required to determine the severity of coinfections at later time points. The findings of this study are in line with previous reports that showed viral-induced changes to the number or functionality of AMΦs might be due to IFN, which makes them less efficient to clear bacteria.
Scientists have indicated that more studies are required to understand how a productive SARS-CoV-2 infection of AMΦ changes infection dynamics. Additionally, the impact of the altered production of IFN and their phagocytic capacity need to be further studied. IFN-independent mechanisms of macrophage dysfunction should be examined to understand the severity of coinfection.
Scientists believe that viral-induced changes in bacterial receptor expression and binding, as well as the degradation of epithelial integrity, could facilitate bacterial adherence during IAV and SARS-CoV-2 infection.
The current study revealed that type I IFNs remained unchanged after SARS-CoV-2-pneumococcal coinfection. However, neutrophil infiltration was reported in coinfection at seven days pvi, which indicated a differential mechanism is associated with enhanced pathogenicity of SARS-CoV-2 pneumococcal coinfection.
Interestingly, researchers observed that cytokine production was largely unchanged at 24 hours pvi. Researchers indicated that even though coinfections are generally linked with hyper inflammation with enhanced disease severity, this was not the case with SARS-CoV-2 or influenza-pneumococcal coinfections, where tissue inflammation was not altered.
The findings of the current study strongly indicated an increased susceptibility of SARS-CoV-2-infected individuals to bacterial infection in a time-dependent manner with increased disease severity, pulmonary bacterial burden, bacteremia, and neutrophilia. The findings of this study are extremely important, especially due to a sustained immune activation after coinfection, which might increase the risk of developing acute respiratory distress syndrome even in patients with mild COVID-19.