RESEARCH

The broad scope of our research is understanding host-pathogen interactions. We currently work with the bacterium, Staphylococcus aureus, a major human pathogen responsible for a broad range of diseases including pneumonia, bloodstream and skin and soft tissue infections. We investigate the interaction of S. aureus with the host innate immune system. Our studies take a multi-disciplinary approach that includes both in vitro and in vivo techniques that span microbiology, immunology and molecular biology.

 

Type I and III interferons

 

Type I interferon (IFN) signaling often involves the activation of an intracellular (endosomal or cytosolic) sensor that initiates the activation of IFN-b via several different interferon regulator factor (IRF) transcriptional activators, i.e. it senses organisms or PAMPs that have infiltrated the cell. Interaction of IFN-b with its heterodimeric receptors (interferon alpha/beta receptor, IFNAR) results in dimerisation and phosphorylation of STAT1/2 via Jak1 and Tyk2 leading to the downstream transcription of hundreds of genes. Type I IFN signaling has traditionally been associated with viral infection but it is now appreciated that bacteria and their products are also able to activate this pathway. Many bacterial pathogens, both intra- and extracellular are able to induce a type I IFN response via recognition of PAMPs and messengers such as DNA, RNA, peptidoglycan, LPS and cyclic diadenosine monophosphate (c-di-AMP). TLR2, 3, 4, 7, 8, 9, NOD, RNA polymerase III and stimulator of interferon genes (STING) are among the many sensors involved in activating the type I IFN response. Type I interferons exert their effect on a variety of cell types influencing cell function and antimicrobial production.

 

Type III IFN signaling (IFN-λ) utilizes many of the same receptors and triggers as type I IFN signaling. The IFN-λ members [IL-28A/B and IL-29 (only in humans)] signal through the IL-28 receptor (IL-28R or IFNLR) that is primarily located on epithelial cells in contrast to IFNAR that is ubiquitous. Although type I and III IFNs have distinct receptors they converge to phosphorylate STAT1/2 and thus activate similar transcripts. What differs in the transcriptome of type I and III IFN is the intensity and duration of the response. Type I is activated early and strongly and type III is induced over time at lower levels.

 

We have shown that both type I and type III IFN signaling contributes to the pathogenesis of S. aureus infection in the context of acute pneumonia. We have also demonstrated that the ability of S. aureus to activate the type I IFN response is correlated with virulence and damage to the lung. Different strains of S. aureus are also able to activate different levels of type I IFN and they each activate through different signaling pathways. Prior infection with influenza also significantly increases the susceptibility of mice to infection with S. aureus and both type I and III IFN are major contributors this increases in susceptibility.

 

Current studies focused on the interferons are aimed at examining the mechanism behind their role in the pathogenesis of S. aureus pneumonia. How they influence cellular influx, cytokine production and cell function and how this influences the outcome on infection. We have also begun studies examining the upper respiratory tract and the role the interferons play in the context of influenza superinfection and colonization of S. aureus.

 

​Skin infections

 

S. aureus is the major cause of skin and soft tissue infections and we have begun some studies to investigate its interaction with keratinocytes and in the context of infection. We have observed that keratinocytes are capable of activating the caspase-1-depedent pyroptosis pathway and this facilitates invasion across the keratinocyte barrier. Strains that are unable to activate the inflammasome through toxin-mutation for example, are able to persist intracellularly within keratinocytes. Current studies are focused on the ability of S. aureus to cause infections in the context of diabetes, the effect of this dysregulated environment on S. aureus physiology, as well as the host innate immune system and its ability to clear infections.

Acinetobacter baumannii

A. baumannii is another critically important pathogen as recognized by the CDC for its multi-drug resistant capacity and ability to cause opportunistic infections. We have begun to develop in vivo models to better examine the contribution type I and III IFNs play in the host response to this organism as well as dissecting bacterial factors important in its defense against the host response.

Role of innate immune cells

We are also actively investigating the contribution of different innate immune cells, such as alveolar macrophages, monocytes, neutrophils and dendritic cells in respiratory infection. How these cells alter their properties during and after infection and how this impacts their function and differentiation over time. We are currently investigating the phenomenon of innate immune training, whereby innate cells can retain a "memory" of prior exposure to give an improved anti-bacterial response to subsequent infection,

Identification of novel virulence factors

S. aureus is of considerable clinical concern due to its significant morbidity and mortality as well as its resistance to antibiotics. Attempts at developing a suitable vaccine have not been successful to date. This would suggest that although many virulence factors of S. aureus have been identified and well studied, other uncharacterized products important in infection are ill-defined. To identify new virulence factors of S. aureus we have conducted a genome wide Tn-seq screen. This has identified over 100 genes that appear to be important for in vivo fitness in an animal model of acute pneumonia. We are currently characterizing these genes and their role in various in vitro and in vivo assays to better define their roles in pathogenesis.

Contact us

© 2016 Dane Parker

205 South Orange Ave

G-level, 1208

Newark, NJ 07103.

USA

Office: 973-972-3047

Lab: 973-972-3336

Email: dane.parkerATrutgers.edu