University Of Tennessee Study Warns That Mild SARS-CoV-2 Infection Increases Risk Of Opportunistic Pneumococcal Coinfection

A new study conducted by researchers from University of Tennessee Health Science Center-USA has found that even mild SARS-CoV-2 infections increase the risk of opportunistic pneumococcal coinfection and in many cases, those affected are unaware till their conditions deteriorates in the late stages.


 
Typically, secondary bacterial infections can exacerbate SARS-CoV-2 infection, but their prevalence and impact remain poorly understood.
 
The study team established that a mild to moderate SARS-CoV-2 infection increased the risk of pneumococcal coinfection in a time-dependent, but sex independent, manner in the transgenic K18-hACE mouse model of COVID-19.
 
The study findings found that bacterial coinfection was not established at 3- days post-virus, but increased lethality was observed when the bacteria was initiated at 5- or 7-days post-virus infection (pvi). Bacterial outgrowth was accompanied by neutrophilia in the groups coinfected at 7 d pvi and reductions in B cells, T cells, IL-6, IL-15, IL-18, and LIF were present in groups coinfected at 5 d pvi.
 
Interestingly, viral burden, lung pathology, cytokines, chemokines, and immune cell activation were largely unchanged after bacterial coinfection.
 
Examining surviving animals more than a week after infection resolution suggested that immune cell activation remained high and was exacerbated in the lungs of coinfected animals compared with SARS-CoV-2 infection alone.
 
Corresponding author, Dr Colleen B. Jonsson from the Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center told Thailand Medical News, “The study findings suggest that SARS-CoV-2 increases susceptibility and pathogenicity to bacterial coinfection, and further studies are needed to understand and combat disease associated with bacterial pneumonia in COVID-19 patients.”

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The study findings were published on a preprint server and are currently being peer reviewed. https://www.biorxiv.org/content/10.1101/2022.02.28.482305v1
 
Numerous multi-center cohort studies, systematic reviews, and meta-analyses have been conducted during the ongoing COVID-19 pandemic, which has been caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
 
Most of these studies have focused on determining the possibility and severity of opportunistic coinfections with secondary pathogens (viruses, fungi, and bacteria).
 
Many of these findings yielded observations that coinfection rates varied across different scenar ios.
 
Past studies have also 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). https://pubmed.ncbi.nlm.nih.gov/16631551/
 
https://pubmed.ncbi.nlm.nih.gov/24590244/
 
https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC5481322/
 
https://pubmed.ncbi.nlm.nih.gov/22568716/
 
https://pubmed.ncbi.nlm.nih.gov/23964104/
 
https://pubmed.ncbi.nlm.nih.gov/26216421/
 
Importantly, in another study, researchers detected Pneumococcus from the throat swabs of hospitalized COVID-19 patients who did not require intensive care unit (ICU) admission or ventilator support. https://pubmed.ncbi.nlm.nih.gov/32979617/
 
https://pubmed.ncbi.nlm.nih.gov/32127123/
 
https://pubmed.ncbi.nlm.nih.gov/32408156/
 
https://pubmed.ncbi.nlm.nih.gov/32894364/
 
To date, 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.
 
Certain past 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. https://pubmed.ncbi.nlm.nih.gov/34367190/
 
https://pubmed.ncbi.nlm.nih.gov/33841435/
 
https://pubmed.ncbi.nlm.nih.gov/32810438/
 
It was reported that a prior study used animal models to investigate the viral and immune dynamics in the lower respiratory tract found that bacteria could enhance the pathogenicity of coronaviruses. https://pubmed.ncbi.nlm.nih.gov/18380809/
 
Numerous other 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). https://pubmed.ncbi.nlm.nih.gov/12134230/
 
It was found that 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. https://pubmed.ncbi.nlm.nih.gov/23804714/
 
https://pubmed.ncbi.nlm.nih.gov/27974820/
 
Importantly prior in vitro studies have shown that AMΦs become productively infected with SARS-CoV-2, which initiates altered cytokine production and responsiveness. https://pubmed.ncbi.nlm.nih.gov/32270184/
 
https://www.nature.com/articles/s41421-021-00258-1
https://pubmed.ncbi.nlm.nih.gov/33112036/
 
https://pubmed.ncbi.nlm.nih.gov/33429418/
 
Furthermore, during SARS-CoV-2 infection, myeloid dysfunction, delayed IFN responses, and CD8+ T cell depletion have been reported.
 
Experts 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.
 
This new study by researchers from University of Tennessee Health Science Center has evaluated bacterial susceptibility during SARS-CoV-2 infection. It further determined if a synergy exists between SARS-CoV-2 and pneumococcus.
 
The study team triggered mild to moderate SARS-CoV-2 infection in K18-hACE2 mice and, subsequently, coinfected them 3, 5, or 7 days later with pneumococcus.
 
The team reported that bacteria failed to establish infection at three days pvi.
 
Interestingly 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.
 
The study team 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 team says that more studies are required to determine the severity of coinfections at later time points.
 
The research 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.
 
The study team have indicated that more studies are required to understand how a productive SARS-CoV-2 infection of AMΦ changes infection dynamics.
 
Also, 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.
 
The study team believes 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 study findings 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.
 
The study team 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 study findings 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.
 
This study findings 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.
 
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