Transmission is a critical component in the life cycle of any successful pathogen and can be considered as the first step towards the carrier- and the disease state. However, it is also one of the least characterized steps because of the inherent complexities in studying natural transmission. Therefore, the goal of our lab is to provide insight into the bacterial or host factors that are associated with mucosal colonization and host-to-host transmission. We believe that an understanding of transmission would allow us new avenues to block the manifestation of the disease state.
Highlighted Research Projects
To broaden our understanding of host-to-host transmission our laboratory utilizes diverse methods that blend bacterial genetics, animal models, molecular, biochemical, and genome-wide approaches. Our transmission studies are carried out by employing two medically notable bacterial pathogens-Klebsiella pneumoniae (Kpn) and Streptococcus pneumoniae (Spn).
Klebsiella pneumoniae (Kpn)
Antimicrobial resistance is now considered a public health crisis. In the United States alone over 2 million people are infected with antibiotic-resistant bacteria, of which over 23,000 succumb to their infections. For this reason both the World Health Organization (WHO) and the Centers for Disease Control (CDC) have labeled fighting antimicrobial resistance a “public health priority.” K. pneumoniae a gram-negative, highly antibiotic resistant bacterium is one of the leading cause of hospital acquired infections. It readily colonizes the mucosal surfaces of humans and animals, and is extremely transmissible in a hospital setting.
The emphasis of most studies tend to be on Kpn associated disease state. Our novel approach, focuses on developing an animal model for Kpn gastro-intestinal colonization and characterizing host-to-host transmission events occurring through the fecal-oral route. Epidemiological studies have demonstrated that gut colonization of the host is the first step before disease manifestations arise at distal sites. Using our animal model, we are identifying and defining the role of bacterial and host factors that contribute towards Kpn’s dissemination.
Streptococcus pneumoniae (Spn)
Pneumococcus remains one of the leading causes of morbidity and mortality in young children, the elderly and the immune compromised worldwide. Spn colonizes the mucosal surface of the upper respiratory tract of its obligate human host. From this site, Spn can disseminate to other locations within the host and cause disease manifestations. The advent of the pneumococcal conjugate vaccine (PCV) led to a massive reduction in the total number of cases. However, even with the availability of this and other vaccines, the number of acute disease cases is still considerably high, with over half a million deaths recorded in children under the age of 5.
Pneumococcus is highly transmissible with a concurrent viral infection, especially in a crowded setting such as daycare centers. To study pneumococcal transmission, we developed an infant mouse model that recapitulates many of the essential requirements for human transmission (proximity, occurring in the young, and high transmission rates with viral co-infection). We are using this model to identify the de novo transcriptional changes that occur during colonization, which eventually lead to host-to-host transmission. Pneumococcal transcriptional factors remain poorly characterized and we aim to define their role in asymptomatic colonization and also to identify potential new targets for drug development.
Zafar, M. A., A. J. Hammond, S. Hamaguchi, W. S. Wu, M. Kono, L. L. Zhao and J. N. Weiser (2019). "Identification of Pneumococcal Factors Affecting Pneumococcal Shedding Shows that the dlt Locus Promotes Inflammation and Transmission." Mbio 10(3).
Hamaguchi, S., M. A. Zafar, M. Cammer and J. N. Weiser (2018). "Capsule prolongs survival of Streptococcus pneumoniae during starvation." Infect Immun.
Zafar, M. A., S. Hamaguchi, T. Zangari, M. Cammer and J. N. Weiser (2017). "Capsule Type and Amount Affect Shedding and Transmission of Streptococcus pneumoniae." MBio 8(4).
Zafar, M. A., Y. Wang, S. Hamaguchi and J. N. Weiser (2017). "Host-to-Host Transmission of Streptococcus pneumoniae Is Driven by Its Inflammatory Toxin, Pneumolysin." Cell Host & Microbe 21(1): 73-83.
Zafar, M. A., M. Kono, Y. Wang, T. Zangari and J. N. Weiser (2016). "Infant Mouse Model for the Study of Shedding and Transmission during Streptococcus pneumoniae Monoinfection." Infect Immun 84(9): 2714-2722.
Zafar, M. A., V. J. Carabetta, M. J. Mandel and T. J. Silhavy (2014). "Transcriptional occlusion caused by overlapping promoters." Proc Natl Acad Sci U S A 111(4): 1557-1561.