Bender, R. G. et al. Global, regional, and national incidence and mortality burden of non-COVID-19 lower respiratory infections and aetiologies, 1990–2021: a systematic analysis from the Global Burden of Disease Study 2021. Lancet Infect. Dis. 24, 974−1002 (2024).
Kelly, M. S. et al. Association of respiratory viruses with outcomes of severe childhood pneumonia in Botswana. PLoS ONE10, e0126593 (2015).
O’Brien, K. L. et al. Causes of severe pneumonia requiring hospital admission in children without HIV infection from Africa and Asia: the PERCH multi-country case-control study. Lancet 394, 757–779 (2019).
Wahl, B. et al. Burden of Streptococcus pneumoniae and Haemophilus influenzae type b disease in children in the era of conjugate vaccines: global, regional, and national estimates for 2000–15. Lancet Glob. Health 6, e744–e757 (2018).
Chien, Y.-W., Klugman, K. P. & Morens, D. M. Bacterial pathogens and death during the 1918 influenza pandemic. N. Engl. J. Med. 361, 2582–2583 (2009).
Morens, D. M., Taubenberger, J. K. & Fauci, A. S. Predominant role of bacterial pneumonia as a cause of death in pandemic influenza: implications for pandemic influenza preparedness. J. Infect. Dis. 198, 962–970 (2008).
Finelli, L. et al. Influenza-associated pediatric mortality in the United States: increase of Staphylococcus aureus coinfection. Pediatrics 122, 805–811 (2008).
Kallen, A. J. et al. Staphylococcus aureus community-acquired pneumonia during the 2006 to 2007 influenza season. Ann. Emerg. Med. 53, 358–365 (2009).
Zhou, H. et al. Invasive pneumococcal pneumonia and respiratory virus co-infections. Emerg. Infect. Dis. 18, 294 (2012).
Kim, P. E. et al. Association of invasive pneumococcal disease with season, atmospheric conditions, air pollution, and the isolation of respiratory viruses. Clin. Infect. Dis. 22, 100–106 (1996).
Lee, L. N. et al. A mouse model of lethal synergism between influenza virus and Haemophilus influenzae. Am. J. Pathol. 176, 800–811 (2010).
Brockson, M. E. et al. Respiratory syncytial virus promotes Moraxella catarrhalis-induced ascending experimental otitis media. PLoS ONE 7, e40088 (2012).
Brueggemann, A. B. et al. Changes in the incidence of invasive disease due to Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis during the COVID-19 pandemic in 26 countries and territories in the Invasive Respiratory Infection Surveillance Initiative: a prospective analysis of surveillance data. Lancet Digit. Health 3, e360–e370 (2021).
Willen, L., Ekinci, E., Cuypers, L., Theeten, H. & Desmet, S. Infant pneumococcal carriage in Belgium not affected by COVID-19 containment measures. Front. Cell. Infect. Microbiol. 11, 825427 (2022).
Dagan, R. et al. The COVID-19 pandemic as an opportunity for unravelling the causative association between respiratory viruses and pneumococcus-associated disease in young children: a prospective study. EBioMedicine 90, 104493 (2023).
Kelly, M. S. et al. Non-diphtheriae Corynebacterium species are associated with decreased risk of pneumococcal colonization during infancy. ISME J. 16, 655–665 (2021).
Accorsi, E. K. et al. Determinants of Staphylococcus aureus carriage in the developing infant nasal microbiome. Genome Biol. 21, 1–24 (2020).
Stubbendieck, R. M. et al. Rothia from the human nose inhibit Moraxella catarrhalis colonization with a secreted peptidoglycan endopeptidase. mBio 14, e00464–00423 (2023).
Jacoby, P. et al. Modelling the co-occurrence of Streptococcus pneumoniae with other bacterial and viral pathogens in the upper respiratory tract. Vaccine 25, 2458–2464 (2007).
Pettigrew, M. M., Gent, J. F., Revai, K., Patel, J. A. & Chonmaitree, T. Microbial interactions during upper respiratory tract infections. Emerg. Infect. Dis. 14, 1584 (2008).
Shiri, T. et al. Interrelationship of Streptococcus pneumoniae, Haemophilus influenzae and Staphylococcus aureus colonization within and between pneumococcal-vaccine naïve mother-child dyads. BMC Infect. Dis. 13, 483 (2013).
Nzenze, S. et al. Temporal association of infant immunisation with pneumococcal conjugate vaccine on the ecology of Streptococcus pneumoniae, Haemophilus influenzae and Staphylococcus aureus nasopharyngeal colonisation in a rural South African community. Vaccine 32, 5520–5530 (2014).
Chien, Y. W. et al. Density interactions among Streptococcus pneumoniae, Haemophilus influenzae and Staphylococcus aureus in the nasopharynx of young Peruvian children. Pediatr. Infect. Dis. J. 32, 72–77 (2013).
Dunne, E. M. et al. Carriage of Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Staphylococcus aureus in Indonesian children: a cross-sectional study. PloS one 13, e0195098 (2018).
McNally, L. M. et al. Lack of association between the nasopharyngeal carriage of Streptococcus pneumoniae and Staphylococcus aureus in HIV-1–infected South African children. J. Infect. Dis. 194, 385–390 (2006).
Douglas, G. M. et al. PICRUSt2 for prediction of metagenome functions. Nat. Biotechnol. 38, 685–688 (2020).
Soeters, H. M. et al. Current epidemiology and trends in invasive haemophilus influenzae disease—United States, 2009–2015. Clin. Infect. Dis. 67, 881–889 (2018).
Mohanty, S. et al. Incidence of pneumococcal disease in children ≤48 months old in the United States: 1998–2019. Vaccine 42, 2758–2769 (2024).
Mohanty, S. et al. Incidence of acute otitis media from 2003 to 2019 in children≤ 17 years in England. BMC public health 23, 201 (2023).
Hu, T. et al. Incidence of acute otitis media in children<16 years old in Germany during 2014–2019. BMC Pediatr. 22, 204 (2022).
Bogaert, D., de Groot, R. & Hermans, P. Streptococcus pneumoniae colonisation: the key to pneumococcal disease. Lancet Infect. Dis. 4, 144–154 (2004).
Kelly, M. et al. The effect of exposure to wood smoke on outcomes of childhood pneumonia in Botswana. Int. J. Tuberc. Lung Dis. 19, 349–355 (2015).
Kelly, M. S. et al. Treatment failures and excess mortality among HIV-exposed, uninfected children with pneumonia. J. Pediatric. Infect. Dis. Soc. 4, e117–e126 (2014).
Vu, H. T. T. et al. Association between nasopharyngeal load of Streptococcus pneumoniae, viral coinfection, and radiologically confirmed pneumonia in Vietnamese children. Pediatr. Infect. Dis. J. 30, 11–18 (2011).
Baggett, H. C. et al. Density of upper respiratory colonization with Streptococcus pneumoniae and its role in the diagnosis of pneumococcal pneumonia among children aged <5 years in the PERCH study. Clin. Infect. Dis. 64, S317–S327 (2017).
Short, K. R., Reading, P. C., Wang, N., Diavatopoulos, D. A. & Wijburg, O. L. Increased nasopharyngeal bacterial titers and local inflammation facilitate transmission of Streptococcus pneumoniae. mBio 3, 00255–00212 (2012).
Chonmaitree, T. et al. Symptomatic and asymptomatic respiratory viral infections in the first year of life: association with acute otitis media development. Clin. Infect. Dis. 60, 1–9 (2014).
Newton, A. H., Cardani, A. & Braciale, T. J. The host immune response in respiratory virus infection: balancing virus clearance and immunopathology. Semin. Immunopathol. 38, 471–482 (2016).
Taubenberger, J. K. & Morens, D. M. The pathology of influenza virus infections. Annu. Rev. Pathol. Mech. Dis. 3, 499–522 (2008).
Kennedy, J. L., Turner, R. B., Braciale, T., Heymann, P. W. & Borish, L. Pathogenesis of rhinovirus infection. Curr. Opin. Virol. 2, 287–293 (2012).
Novotny, L. A. & Bakaletz, L. O. Intercellular adhesion molecule 1 serves as a primary cognate receptor for the Type IV pilus of nontypeable Haemophilus influenzae. Cell. Microbiol. 18, 1043–1055 (2016).
Ishizuka, S. et al. Effects of rhinovirus infection on the adherence of Streptococcus pneumoniae to cultured human airway epithelial cells. J. Infect. Dis. 188, 1928–1939 (2003).
Glennie, S. et al. Modulation of nasopharyngeal innate defenses by viral coinfection predisposes individuals to experimental pneumococcal carriage. Mucosal Immunol. 9, 56–67 (2016).
Cusumano, J. A. et al. Staphylococcus aureus Bacteremia in patients infected with COVID-19: a case series. Open Forum Infect. Dis. 7, ofaa518 (2020).
Bassetti, M., Magnasco, L., Vena, A., Portunato, F. & Giacobbe, D. R. Methicillin-resistant Staphylococcus aureus lung infection in coronavirus disease 2019: how common?. Curr. Opin. Infect. Dis. 35, 149–162 (2022).
Hall-Stoodley, L. et al. Direct detection of bacterial biofilms on the middle-ear mucosa of children with chronic otitis media. JAMA: J. Am. Med. Assoc. 296, 202–211 (2006).
Thornton, R. B. et al. Multi-species bacterial biofilm and intracellular infection in otitis media. BMC Pediatric.11, 1–10 (2011).
Cope, E. K. et al. Regulation of virulence gene expression resulting from Streptococcus pneumoniae and nontypeable Haemophilus influenzae interactions in chronic disease. PLoS ONE6, e28523 (2011).
Schaar, V., Nordström, T., Mörgelin, M. & Riesbeck, K. Moraxella catarrhalis outer membrane vesicles carry β-lactamase and promote survival of Streptococcus pneumoniae and Haemophilus influenzae by inactivating amoxicillin. Antimicrobial. Agents Chemother. 55, 3845–3853 (2011).
Esposito, S. et al. Streptococcus pneumoniae and Staphylococcus aureus carriage in healthy school-age children and adolescents. J. Med. Microbiol. 64, 427–431 (2015).
Murad, C. et al. Pneumococcal carriage, density, and co-colonization dynamics: a longitudinal study in Indonesian infants. Int. J. Infect. Dis. 86, 73–81 (2019).
Kaur, R. & Pichichero, M. Colonization, density, and antibiotic resistance of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis among PCV13-vaccinated infants in the first six months of life in Rochester, New York: a cohort study. J. Pediatr. Infect. Dis. Soc. 12, 135–142 (2023).
O’Brien, K. L. et al. Effect of pneumococcal conjugate vaccine on nasopharyngeal colonization among immunized and unimmunized children in a community-randomized trial. J. Infect. Dis. 196, 1211–1220 (2007).
Hurst, J. H. et al. Serotype epidemiology and antibiotic resistance of pneumococcal isolates colonizing infants in Botswana (2016-2019). PLoS ONE19, e0302400 (2024).
Dunne, E. M. et al. Effect of ten-valent pneumococcal conjugate vaccine introduction on pneumococcal carriage in Fiji: results from four annual cross-sectional carriage surveys. Lancet Glob. Health 6, e1375–e1385 (2018).
Roca, A. et al. Effect of age and vaccination with a pneumococcal conjugate vaccine on the density of pneumococcal nasopharyngeal carriage. Clin. Infect. Dis. 55, 816–824 (2012).
von Mollendorf, C. et al. Pneumococcal carriage in children in Ulaanbaatar, Mongolia before and one year after the introduction of the 13-valent pneumococcal conjugate vaccine. Vaccine 37, 4068–4075 (2019).
Chen, A. E. et al. Evolving epidemiology of pediatric Staphylococcus aureus cutaneous infections in a Baltimore hospital. Pediatr. Emerg. Care 22, 717–723 (2006).
Kakar, N., Kumar, V., Mehta, G., Sharma, R. C. & Koranne, R. V. Clinico-bacteriological study of pyodermas in children. J. Dermatol. 26, 288–293 (1999).
Rogers, M., Dorman, D. C., Gapes, M. & Ly, J. A three-year study of impetigo in Sydney. Med. J. Aust. 147, 63–65 (1987).
de Steenhuijsen Piters, W. A. A. et al. Early-life viral infections are associated with disadvantageous immune and microbiota profiles and recurrent respiratory infections. Nat. Microbiol. 7, 224–237 (2022).
Kelly, M. S. et al. Pneumococcal colonization and the nasopharyngeal microbiota of children in Botswana. Pediatr. Infect. Dis. J. 37, 1176–1183 (2018).
Bomar, L., Brugger, S. D., Yost, B. H., Davies, S. S. & Lemon, K. P. Corynebacterium accolens releases antipneumococcal free fatty acids from human nostril and skin surface triacylglycerols. mBio 7, e01725–01715 (2016).
Hardy, B. L. et al. Corynebacterium pseudodiphtheriticum exploits Staphylococcus aureus virulence components in a novel polymicrobial defense strategy. mBio 10, 02491–02418 (2019).
Kiryukhina, N., Melnikov, V., Suvorov, A., Morozova, Y. A. & Ilyin, V. Use of Corynebacterium pseudodiphtheriticum for elimination of Staphylococcus aureus from the nasal cavity in volunteers exposed to abnormal microclimate and altered gaseous environment. Probiotics Antimicrobial. Proteins 5, 233–238 (2013).
Shekhar, S., Khan, R., Schenck, K. & Petersen, F. C. Intranasal immunization with the commensal streptococcus mitis confers protective immunity against pneumococcal lung infection. Appl. Environ. Microbiol. 85, e02235–02218 (2019).
Mathieu, E. et al. An isolate of Streptococcus mitis displayed in vitro antimicrobial activity and deleterious effect in a preclinical model of lung infection. Nutrients 15, 263 (2023).
Khamash, D. F. et al. The association between the developing nasal microbiota of hospitalized neonates and staphylococcus aureus colonization. Open Forum Infect. Dis. 6, ofz062 (2019).
Brugger, S. D. et al. Dolosigranulum pigrum cooperation and competition in human nasal microbiota. Msphere 5, e00852-20 (2020).
Khamash, D. F. et al. Low diversity in nasal microbiome associated with Staphylococcus aureus colonization and bloodstream infections in hospitalized neonates. Open forum Infect. Dis. 8, ofz062 (2021).
Mitsi, E. et al. RSV and rhinovirus increase pneumococcal carriage acquisition and density, whereas nasal inflammation is associated with bacterial shedding. Cell Host Microbe 32, 1608−1620.e4 (2024).
Robinson, R. E. et al. Human infection challenge with serotype 3 pneumococcus. Am. J. Resp. Crit. Care Med. 206, 1379–1392 (2022).
Desai, H. et al. Bacterial colonization increases daily symptoms in patients with chronic obstructive pulmonary disease. Ann. Am. Thorac. Soc. 11, 303–309 (2014).
Yoshida, M. et al. Local and systemic responses to SARS-CoV-2 infection in children and adults. Nature 602, 321–327 (2022).
Hurst, J. H. et al. Differential host responses within the upper respiratory tract and peripheral blood of children and adults with SARS-CoV-2 infection. medRxiv5, 2023.07.31.23293337 (2023).
Byington, C. L. et al. Community surveillance of respiratory viruses among families in the Utah better identification of germs-longitudinal viral epidemiology (BIG-LoVE) study. Clin. Infect. Dis. 61, 1217–1224 (2015).
Kalu, S. U. et al. Persistence of adenovirus nucleic acids in nasopharyngeal secretions: a diagnostic conundrum. Pediatr. Infect. Dis. J. 29, 746–750 (2010).
Statistics Botswana. 2022 Population and Housing Census: Preliminary Results V2. https://www.statsbots.org.bw/sites/default/files/2022%20Population%20and%20Housing%20Census%20Preliminary%20Results.pdf. (2024).
Callahan, B. J. et al. DADA2: high-resolution sample inference from Illumina amplicon data. Nat. Methods 13, 581 (2016).
Escapa, I. F. et al. New insights into human nostril microbiome from the expanded human oral microbiome database (eHOMD): a resource for the microbiome of the human aerodigestive tract. Msystems 3, e00187–00118 (2018).
Moossavi, S., Fehr, K., Khafipour, E. & Azad, M. B. Repeatability and reproducibility assessment in a large-scale population-based microbiota study: case study on human milk microbiota. Microbiome 9, 41 (2021).
Leoni, C. et al. Human endometrial microbiota at term of normal pregnancies. Genes 10, 971 (2019).
Glassing, A., Dowd, S. E., Galandiuk, S., Davis, B. & Chiodini, R. J. Inherent bacterial DNA contamination of extraction and sequencing reagents may affect interpretation of microbiota in low bacterial biomass samples. Gut Pathog. 8, 1–12 (2016).
Davis, N. M., Proctor, D. M., Holmes, S. P., Relman, D. A. & Callahan, B. J. Simple statistical identification and removal of contaminant sequences in marker-gene and metagenomics data. Microbiome 6, 226 (2018).
Caspi, R. et al. The MetaCyc database of metabolic pathways and enzymes and the BioCyc collection of pathway/genome databases. Nucleic Acids Res. 44, D471–D480 (2016).
Camacho, C. et al. BLAST+: architecture and applications. BMC Bioinforma. 10, 421 (2009).
Mallick, H. et al. Multivariable association discovery in population-scale meta-omics studies. PLoS. Comput. Biol.17, e1009442 (2021).
Kelly M. S.et al. Role of the upper respiratory microbiota in respiratory virus and bacterial pathobiont dynamics. medRxiv 23, 2024.10.22.24315478 (2025).
