Nadeem Khan, Ph.D.

Synopsis. The focus of our laboratory is to better define the role of host responses and inflammation in the context of respiratory pathogens, primarily influenza virus and Streptococcus pneumoniae (pneumococcus or Spn). Secondary bacterial infections constitute the major cause of morbidity and mortality in influenza-infected humans, and the Center for Disease Control (CDC) recommends the use of pneumococcal and influenza vaccines in people with respiratory conditions or >65 years. Severe influenza or viral-bacterial pneumonia manifestations include profound airway lung and vascular injuries that impact gas exchange and require hospitalization. Most of these complications are attributed to the host’s own defense mechanisms because host responses while executing the pathogen drive collateral lung damage. Therefore, the pathologic host response implicated in airway/lung damage is at the heart of renewed emphasis towards developing better treatment strategies to contain influenza and secondary bacterial disease. Using mouse models of influenza and secondary bacterial infections, we strive to understand the crucial interplay between inflammatory myeloid and lymphoid cells and their communications with non-hematopoietic cells (epithelial cells) that result in acute airway damage and permissiveness of inflamed/damaged airway tissues for secondary bacterial infections.

Current Projects.

1. CD8+ T cell responses and influenza viral pneumonia. Data from the 2009 H1N1 pandemic show a strong correlation of the increased numbers/responses of CD8+ T cells with influenza disease severity. However, mice with impaired CD8+ T cell responses eventually succumb to the infection due to their inability to control the viral load. Thus, paradoxically, CD8+ T cells while indispensable to influenza control, also contribute to the significant lung pathology that exacerbates the disease. Our investigations are focused on identifying the protective vs pathologic CD8+ T cell subsets contributing to viral clearance or immune-mediated lung pathology. We are actively investigating the key roles of interferons (IFNs), IFN-associated transmembrane proteins, and inflammatory monocytes in the regulation of CD8+ T cell effector vs memory fates during influenza viral pneumonia. We use a wide range of cutting-edge advanced technologies such as single-cell genomics and spatial transcriptome and mouse models of conditional gene deletions to address the fundamental questions in our lab. We expect that our work will create new frontiers in basic and translational directions and open new avenues to develop more effective vaccines and therapeutics against influenza viral pneumonia and influenza-associated secondary bacterial diseases.

2. Pathogenesis of Streptococcus pneumoniae. Streptococcus pneumoniae (Spn) causes a variety of infections in humans, including otitis media, sinusitis, pneumonia, and life-threatening invasive pneumococcal diseases, such as sepsis and meningitis. Nasopharyngeal (NP) colonization is a precursor for Spn disease, and coinfection with influenza virus is a significant risk factor for the development of Spn disease. We have recently discovered that influenza triggers a robust IL-17 response in the upper respiratory nasopharynx causing substantial acute injury and making the nasopharyngeal tissue environment permissive to increased Spn colonization and invasive infection. We are actively investigating how IL-17-driven inflammatory mechanisms contribute to nasopharyngeal epithelial inflammation/injury, leading to Spn disease development.

3. Vaccine development against Streptococcus pneumoniae infections. Another major focus of the laboratory is the development of a protein-based vaccine against Spn diseases. Currently available capsule-based pneumococcal vaccines offer limited efficacy due to the emergence of non-vaccine Spn serotypes and limited serotype coverage in the commercially available PCV (Spn) vaccines. Since Spn bacteria exist in over 90 serotypes, the next-generation protein-based vaccines could offer serotype-independent protection. However, the protein vaccines need to be optimally supplemented with potent adjuvants to enhance the immunogenicity and persistence of antigen-specific protective responses. We have recently developed a novel adjuvanted trivalent protein-based vaccine against pneumococcus, and we are currently evaluating the immunogenicity and protective efficacy of our trivalent vaccine. Furthermore, for the past several years, our group has been evaluating the immune response to new PCV vaccines from Merck, which are currently in clinical trials. Previously, we identified the role of several Spn surface proteins in bacterial adherence (Pht proteins, PcpA), and some of those vaccine candidates were transitioned to clinical trials held in Bangladesh. We expect the future pneumococcal vaccine work in our lab will advance the field with the potential to transition to clinical trials in the near future.

0000-0001-7870-4989

• Host-pathogen interaction
• Lung mucosal immunology
• Regenerative medicine
• Respiratory polymicrobial infections
• Vaccine immunology