Host-directed therapies and antimicrobial drug screening against infectious diseases

David Pires, PhD dpires@ucp.pt ORCID: 0000-0001-9602-1516

In our lab, we are interested in probing the complex interactions between humans and microbes and how those interactions may influence the development of disease. As traditional antibiotic therapies suffer from the rise of drug-resistant strains, our lab takes a complementary approach to find targets in our own cells and processes that can be manipulated to boost the immune response in favor of the host.

To this end, we follow two complementary strategies: The first one is developing host-directed strategies to improve the immune response to microbial pathogens, particularly targeting the cells that bridge innate and adaptive immunity, such as macrophages, dendritic cells, and T-cells. These cells participate in the surveillance and clearance of pathogens but also intervene in the generation of long-lasting protective immunity. How some pathogens, such as the tuberculosis bacilli, are able to interfere with these cells to improve their survival informs us of potential targets we can use to develop host-directed therapies.

The second strategy is screening for new engineered antimicrobial molecules, repurposed drugs, and drug delivery strategies. Antibiotics are still the greatest weapon to treat bacterial infections and finding new molecules that reduce the toxic effects of the treatment, overcome current drug resistance mechanisms, and prevent the evolution of drug-resistant strains is of paramount importance.

The combination of these two approaches, targeting both pathogen and host will be fundamental to improving therapeutic efficacy and reducing the rising burden of drug resistance.
 

Keywords: Immunology; Cellular microbiology; Host-directed therapies; Compound screening; Drug resistance; Tuberculosis; HIV.

Selected references

Pires D., Calado M., Velez T., Mandal M., Catalão M.J., Neyrolles O., Lugo-Villarino G., Vérollet C., Azevedo-Pereira J.M., Anes E. Modulation of Cystatin C in Human Macrophages Improves Anti-Mycobacterial Immune Responses to Mycobacterium tuberculosis Infection and Coinfection With HIV (2021), Frontiers in Immunology, 12, art. no. 742822. DOI: 10.3389/fimmu.2021.742822.

Pires D., Valente S., Calado M., Mandal M., Azevedo-Pereira J.M., Anes E. Repurposing Saquinavir for Host-Directed Therapy to Control Mycobacterium Tuberculosis Infection (2021), Frontiers in Immunology, 12, art. no. 647728. DOI: 10.3389/fimmu.2021.647728.

Pais J.P., Policarpo M., Pires D., Francisco A.P., Madureira AM., Testa B., Anes E., Constantino L. Fluoroquinolone Derivatives in the Treatment of Mycobacterium tuberculosis Infection (2022). Pharmaceuticals, 15(10), pp. 1213. DOI:10.3390/ph15101213.

Santos A.A., Afonso M.B., Ramiro R.S., Pires D., Pimentel M., Castro R.E., Rodrigues C.M.P. Host miRNA-21 promotes liver dysfunction by targeting small intestinal Lactobacillus in mice (2020). Gut Microbes, 12 (1), pp. 1 - 18. DOI: 10.1080/19490976.2020.1840766.

Pires D., Bernard E.M., Pombo J.P., Carmo N., Fialho C., Gutierrez M.G., Bettencourt P., Anes E. Mycobacterium tuberculosis modulates miR-106b-5p to control Cathepsin S expression resulting in higher pathogen survival and poor T-cell activation (2017). Frontiers in Immunology, 8 (DEC), art. no. 1819. DOI: 10.3389/fimmu.2017.01819.

Pires D., Marques J., Pombo J.P., Carmo N., Bettencourt P., Neyrolles O., Lugo-Villarino G., Anes E. Role of Cathepsins in Mycobacterium tuberculosis Survival in Human Macrophages (2016). Scientific Reports, 6, art. no. 32247. DOI: 10.1038/srep32247.

Machado D., Pires D., Perdigão J., Couto I., Portugal I., Martins M., Amaral L., Anes E., Viveiros M. Ion channel blockers as antimicrobial agents, efflux inhibitors, and enhancers of macrophage killing activity against drug resistant mycobacterium tuberculosis (2016) PLoS ONE, 11 (2), art. no. e0149326. DOI: 10.1371/journal.pone.0149326.

Pires D., Valente E., Simões M.F., Carmo N., Testa B., Constantino L., Anes E. Esters of pyrazinoic acid are active against pyrazinamide-resistant strains of Mycobacterium tuberculosis and other naturally resistant mycobacteria in vitro and ex vivo within macrophages (2015). Antimicrobial Agents and Chemotherapy, 59 (12), pp. 7693 - 7699. DOI: 10.1128/AAC.00936-15.