The focus of our laboratory is to understand the pathogenesis of Streptococcus pneumoniae (Spn), a major respiratory bacterial pathogen associated with significant morbidity and mortality both in the US and globally. Children under the age of five years, elderly, and immune-compromised constitute vulnerable human subsets who are at an increased risk of getting invasive Spn infections. Capsule based vaccines are available for Spn infections, but their efficacy is limited. Additionally, the evolution of new Spn serotypes poses an ongoing challenge to the efficacy and sustenance of existing vaccines. Therefore, new age vaccines and therapeutics are highly required to prevent Spn infections. Spn infections are usually precipitated by some risk factor (usually an inflammatory event) that allows the transition of a commensal Spn into an active pathogen, causing infections of varying severity from sinusitis to pneumonia and sepsis. Respiratory co-infection by Influenza A Virus (IAV) is one of the most significant risk factor for the commencement of concurrent or secondary Spn infections. The early events of airway IAV infection are sensed by a complex network of innate lymphoid and myeloid cells, leading to an overwhelming recruitment of inflammatory monocytes and neutrophils that promote damaging inflammation in the nasopharynx (NP) and lungs. Influenza induced tissue pathology eventually culminates into creating a breeding ground for Spn and other bacterial infections. Using infant and adult mouse IAV/Spn co-infection models of natural Spn pathogenesis, we are pursuing the following research themes:
1) Determine the role of inflammatory risk factors in Spn pathogenesis: We have observed a double edge function of interleukin 17A (IL-17A) in our infection models. While IL-17A conditionally protected against Spn infections, its implication in influenza induced immune pathology might contribute to concurrent or post influenza bacterial infections. Our studies are aimed at further defining the role of IL-17A induced airway inflammation in IAV-Spn co-pathogenesis. A better understanding of inflammatory risk factors, and protective elements of host immunity will lead to the development of novel interventional therapeutics and vaccines to combat severe Spn infections.
2) Natural immunity to Spn infections: A significant gap lies in our understanding as to how human hosts generates a naturally protective immunity to Spn infections. The current work in our lab is designed to understand the contribution of anti-capsular and non-capsular immunity in the prevention of Spn colonization, pneumonia, and sepsis. We are particularly interested in further establishing the role of natural and vaccine-acquired antigen specific CD4+ T cells and antibodies in the prevention of Spn infections that manifest in the context of an inflammatory risk factor.
3) Human Respiratory Microbiome: The other major focus of our lab is to understand the impact of pneumococcal conjugate vaccines (PCVs) on the dynamics of respiratory microbiota. The introduction of PCVs in children has resulted into a substantial reduction of pneumococcal disease burden of vaccine serotypes. However, emergence of non-vaccine serotypes has created a new form of nasal microbial competition, which has led to a more virulent evolution of respiratory bacteria other than pneumococcus. Additionally, new colonizing and disease causing pneumococcal strains have emerged that necessitates the modification of existing conjugate vaccine formulations. We are interested in a) profiling an age specific nasal microbiome (bacterial and viral types and quantitative burden) in PCV vaccinated children and b) the correlation of age specific immune maturation (antigen specific) with nasal microbiome and disease incidents, i.e. viral URI, pneumonia, and invasive pneumococcal diseases. A better understanding of these events would result in developing more robust treatment strategies to combat frequent respiratory infections in children.