By Jessica Lu
Respiratory infections are a major cause of mortality across the world. In 2015, lower respiratory tract infections were estimated to cause 2.74 million deaths worldwide.1 Viral respiratory tract infections are frequently linked to secondary bacterial infections that develop during or following the initial viral infection.2-4 For example, during the SARS-CoV-2 epidemic, at least one in seven COVID-19 patients also developed a secondary bacterial infection.4 Staphylococcus aureus, Streptococcus pneumoniae, Neisseria meningitides, Haemophilus influenzae and Klebsiella pneumoniae are bacteria that are commonly involved in secondary bacterial infections following viral respiratory infection.2 As a result of secondary bacterial infection, the patient suffers from the complications of two different pathogens. This is associated with high morbidity and high mortality rates.2 In fact, untreated or untreatable secondary bacterial infections caused 50% of fatalities during the SARS-CoV-2 epidemic.4 The mechanisms contributing to secondary bacterial infection are complex, involving interactions between viruses, bacteria and the host immune system.5
Firstly, during infection, respiratory viruses damage the respiratory airway both histologically and functionally.5Damage to epithelial cells during viral infection is thought to promote secondary bacterial infection. In animal models, respiratory syncytial virus (RSV) and influenza infection lead to epithelium damage, resulting in higher susceptibility to S. pneumoniae and S. aureus infection.3 The epithelium is normally an impermeable barrier for inhaled pathogens, assembled by tight junctions between cells. However, following viral infection, animal models have shown desquamation, loss of cilia, immune cells infiltration, and necrosis.3 The tight junctions in the epithelium can be damaged by viruses. For example, respiratory syncytial virus (RSV) and influenza viruses can directly or indirectly target proteins involved in tight junctions, including claudin, occludin, or XO-1.3 Viral infections also induce cell apoptosis, contributing to loss of the epithelium barrier.3
Another mechanism for secondary bacterial infection is suppression of the immune system.2-4 Innate immune cells include airway macrophages, monocytes, neutrophils, natural killer cells and dendritic cells.3 Viral infection can deplete and affect the function of innate immune cells, making the host more susceptible to subsequent bacterial infection. For example, influenza virus infection in mice was found to deplete 90% of alveolar macrophages. The remaining 10% of alveolar macrophages were also affected, showing a necrotic phenotype.6 This innate immune defect increased the susceptibility of the mice to S. pneumoniae infection.6 In addition, viral infection can prevent the innate immune system from detecting bacterial pathogens. Innate immune cells use pattern recognition receptors (PRRs) to recognise molecules associated with pathogens. Toll-like receptors (TLRs) are an example of PRRs. Influenza primary viral infection has been found to downregulate various TLRs, such as TLR2, TLR4, and TLR5. As a result, the innate immune response to secondary bacterial infection decreases.3
Although the innate immune response is a first line of defence, adaptive immune responses are crucial to resolve respiratory infection.3 Adaptive immune responses to the initial viral infection may facilitate bacterial secondary infection. For example, during later stages of RSV or influenza infection, the anti-inflammatory cytokine IL-10 is secreted.3 Regulatory T cells may be responsible for this IL-10 secretion. IL-10 secretion has been proposed to inhibit the innate immune response against a second pathogen by regulating neutrophil and macrophage activity.3 CD8+ T cells may also have a detrimental role on the response to bacterial pathogens, since interferon gamma producing T CD8+ cells inhibit the anti-bacterial function of macrophages.3 Lastly, influenza A has been found to inhibit the defence of the Th17 subset of T cells against S. aureus.7 This inhibition is mediated by type I interferons produced due to influenza A infection.7
Finally, another mechanism which facilitates secondary bacterial infection is the enhancement of bacterial adhesion to the respiratory tract. For example, RSV infection increases adherence molecules on infected cell surfaces, enhancing S. pneumoniae adhesion.3 Additionally, RSV can also directly bind pneumococci in an interaction involving the RSV glycoprotein G and the pneumococci cell wall.8 Influenza viruses have three mechanisms to provide potential binding sites for bacteria. Firstly, they cause the up-regulation of bacterial host receptors. Secondly, they cause the host to regenerate the common bacterial receptors fibrin and fibrinogen.5 Thirdly, the influenza virus enzyme neuraminidase cleaves sialic acid from the cell surfaces of host lung cells, exposing receptors for bacterial adherence.5,9
One related issue to secondary bacterial infections is the use of antibiotics for their prevention. For example, almost all seriously ill COVID-19 patients are treated with antibiotics to prevent secondary bacterial infection, even though antibiotics have no effect on the SARS-CoV-2 virus.4 The overuse of antibiotics has a detrimental effect on antibiotic resistance rates, a growing crisis that is endangering patient lives.10 To make matters worse, such prophylactic treatment during severe viral infection often uses antibiotics that target a broad spectrum of bacteria.4 Broad-spectrum antibiotics favour the development of resistance and cause more disruption to the normal microbiome of the host.11Furthermore, the use of antibiotics as a prophylactic treatment is also ineffective when patients acquire antibiotic-resistant strains.4 To counteract these problems, phage therapy has been proposed as a promising alternative prophylactic treatment4, though minimal robust efficacy data is a barrier to phage therapy implementation.12
Overall, the mechanisms underlying secondary bacterial infections following viral respiratory infection are complex, involving interactions between viruses, bacteria, and the host. However, the impacts of secondary bacterial infection on human health are wide. This is especially in light of the rapid increase in antibiotic resistance, which will increasingly prevent effective treatment of secondary bacterial infections. Further study in this area is important to find new diagnostic and therapeutic solutions.
References:
(1) GBD 2015 LRI Collaborators. Estimates of the global, regional, and national morbidity, mortality, and aetiologies of lower respiratory tract infections in 195 countries: a systematic analysis for the Global Burden of Disease Study 2015. The Lancet.Infectious diseases. 2017; 17 (11): 1133-1161. Available from: doi: 10.1016/S1473-3099(17)30396-1.
(2) Manohar P, Loh B, Nachimuthu R, Hua X, Welburn SC, Leptihn S. Secondary Bacterial Infections in Patients With Viral Pneumonia. Frontiers in medicine. 2020; 7 420. Available from: doi:10.3389/fmed.2020.00420.
(3) Oliva J, Terrier O. Viral and Bacterial Co-Infections in the Lungs: Dangerous Liaisons. Viruses. 2021; 13 (9): Available from: doi:10.3390/v13091725.
(4) Manohar P, Loh B, Athira S, Nachimuthu R, Hua X, Welburn SC, et al. Secondary Bacterial Infections During Pulmonary Viral Disease: Phage Therapeutics as Alternatives to Antibiotics? Frontiers in Microbiology. 2020; 11. Available from: doi:10.3389/fmicb.2020.01434.
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(8) Hament J, Aerts PC, Fleer A, van Dijk H, Harmsen T, Kimpen JLL, et al. Direct Binding of Respiratory Syncytial Virus to Pneumococci: A Phenomenon That Enhances Both Pneumococcal Adherence to Human Epithelial Cells and Pneumococcal Invasiveness in a Murine Model. Pediatric Research. 2005; 58 (6): 1198-1203. Available from: doi:10.1203/01.pdr.0000188699.55279.1b.
(9) McCullers JA, Bartmess KC. Role of neuraminidase in lethal synergism between influenza virus and Streptococcus pneumoniae. The Journal of Infectious Diseases. 2003; 187 (6): 1000-1009. Available from: doi:10.1086/368163.
(10) Ventola CL. The antibiotic resistance crisis: part 1: causes and threats. P & T : a peer-reviewed journal for formulary management. 2015; 40 (4): 277-283.
(11) Cižman M, Plankar Srovin T. Antibiotic consumption and resistance of gram-negative pathogens (collateral damage). GMS Infectious Diseases. 2018; 6 Available from: doi:10.3205/id000040.
(12) Mitropoulou G, Koutsokera A, Csajka C, Blanchon S, Sauty A, Brunet J, et al. Phage therapy for pulmonary infections: lessons from clinical experiences and key considerations. European Respiratory Review. 2022; 31 (166): 220121. Available from: doi:10.1183/16000617.0121-2022.
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