The emergence of multidrug resistant bacteria is a major public health concern with increased morbidity and mortality throughout the world. In addition to the search for novel antibiotics, alternative approaches, such as the development of anti-virulence drugs and adjunctive host directed therapies are necessary to fill the antibiotic gap that appeared in the past decade. Our group has focused on multidrug resistant Mycobacterium tuberculosis (Mtb) for which we have developed a drug screening platform that is capable of combining all three approaches in a single assay. Proof of concept studies identified novel Mtb-specific antibiotics, anti-virulence drugs targeting a mycobacterial secretion system, and host directed therapies with novel mode of action. We have extended our innovative screening method to highly drug-resistant Gram-negative bacteria such as Pseudomonas aeruginosa (Pa) and Salmonella enterica serovar Typhimurium (ST) by exploiting their type 3 secretion system (T3SS) dependent host cell killing. Here we could identify several substances showing promising effects on Pa and ST pathogenicity that will provide the basis for future pre-clinical and clinical development with the ultimate goal of tackling the looming antibiotic resistance crisis.

Innate and adaptive immune crosstalk in COVID-19

Our lab has taken part in the worldwide efforts to improve our understanding of COVID-19 and to develop possible treatment and vaccination strategies. More than two and a half years since the occurrence of the first COVID-19 cases, the pandemic is still far from over. The frequent occurrence of new SARS-CoV-2 variants-of-concern renders the existing vaccines less effective, highlighting the urgent need for improved strategies. Data from our recent publications show that both SARS-CoV-2 infection and vaccination prime human macrophages for activation of the NLRP3 inflammasome. Furthermore, we identified spleen tyrosine kinase (SYK) as a regulatory node capable of differentiating between primed and unprimed macrophages, which modulate spike protein specific T cell responses (Figure 1). Importantly, our data show that vaccination induced macrophage priming can be enhanced with repetitive antigen exposure. In further studies, we would like to systematically determine the influence of the innate immune system on the quantity and quality of long-lived antiviral immunity. These data will be important for the development of future vaccines and vaccination regimens against SARS-CoV-2 and other viral pathogens.