Journal Article

Coinfection with Leishmania major and Staphylococcus aureus enhances the pathologic responses to both microbes through a pathway involving IL-17A

Cassel, Suzanne L., Wilson, Mary E., Zhanbolat, Bayan, Horswill, Alexander R., Scorza, Breanna M., Lima Nobre de Queiroz, Fellipe, Parlet, Corey P., Sariol, Alan J., Clay, Gwendolyn M., Chen, Yani, Sutterwala, Fayyaz S., Borbón, Tiffany Y., Bowen, Jayden L., Valadares, Diogo G., Nauseef, William M.

2019

Overview

Cutaneous leishmaniasis (CL) is a parasitic disease causing chronic, ulcerating skin lesions. Most humans infected with the causative Leishmania protozoa are asymptomatic. Leishmania spp. are usually introduced by sand flies into the dermis of mammalian hosts in the presence of bacteria from either the host skin, sand fly gut or both. We hypothesized that bacteria at the dermal inoculation site of Leishmania major will influence the severity of infection that ensues. A C57BL/6 mouse ear model of single or coinfection with Leishmania major, Staphylococcus aureus, or both showed that single pathogen infections caused localized lesions that peaked after 2-3 days for S. aureus and 3 weeks for L. major infection, but that coinfection produced lesions that were two-fold larger than single infection throughout 4 weeks after coinfection. Coinfection increased S. aureus burdens over 7 days, whereas L. major burdens (3, 7, 28 days) were the same in singly and coinfected ears. Inflammatory lesions throughout the first 4 weeks of coinfection had more neutrophils than did singly infected lesions, and the recruited neutrophils from early (day 1) lesions had similar phagocytic and NADPH oxidase capacities. However, most neutrophils were apoptotic, and transcription of immunomodulatory genes that promote efferocytosis was not upregulated, suggesting that the increased numbers of neutrophils may, in part, reflect defective clearance and resolution of the inflammatory response. In addition, the presence of more IL-17A-producing γδ and non-γδ T cells in early lesions (1-7 days), and L. major antigen-responsive Th17 cells after 28 days of coinfection, with a corresponding increase in IL-1β, may recruit more naïve neutrophils into the inflammatory site. Neutralization studies suggest that IL-17A contributed to an enhanced inflammatory response, whereas IL-1β has an important role in controlling bacterial replication. Taken together, these data suggest that coinfection of L. major infection with S. aureus exacerbates disease, both by promoting more inflammation and neutrophil recruitment and by increasing neutrophil apoptosis and delaying resolution of the inflammatory response. These data illustrate the profound impact that coinfecting microorganisms can exert on inflammatory lesion pathology and host adaptive immune responses.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adaptive immunity / Animals / Antigens / Apoptosis / Bacteria / Biology and Life Sciences / Care and treatment / Cells / Coinfection - immunology / Coinfection - microbiology / Coinfection - parasitology / Coinfection - pathology / Concurrent infection / Cutaneous leishmaniasis / Dermis / Ear / Ears / Female / Genes / Genetic aspects / Helper cells / Humans / IL-1β / Immune clearance / Immunology / Immunomodulation / Infections / Inflammation / Inflammatory response / Inoculation / Interdisciplinary aspects / Interleukin-17 - genetics / Interleukin-17 - immunology / Interleukin-1beta - genetics / Interleukin-1beta - immunology / Internal medicine / Leishmania / Leishmania major / Leishmania major - genetics / Leishmania major - isolation & purification / Leishmania major - physiology / Leishmaniasis, Cutaneous / Leishmaniasis, Cutaneous - genetics / Leishmaniasis, Cutaneous - immunology / Leishmaniasis, Cutaneous - parasitology / Leishmaniasis, Cutaneous - pathology / Lesions / Leukocytes (neutrophilic) / Lymphocytes / Lymphocytes T / Medicine / Medicine and Health Sciences / Mice / Mice, Inbred C57BL / Microorganisms / NAD(P)H oxidase / Neutralization / Neutrophils / Neutrophils - immunology / Parasites / Parasitic diseases / Parasitoses / Pathogens / Pathology / Phagocytes / Protozoa / Rats as laboratory animals / Recruitment / Recruitment (fisheries) / Research and Analysis Methods / Resolution / Risk factors / Skin / Skin diseases / Staphylococcal Infections - genetics / Staphylococcal Infections - immunology / Staphylococcal Infections - microbiology / Staphylococcal Infections - pathology / Staphylococcus aureus / Staphylococcus aureus - genetics / Staphylococcus aureus - isolation & purification / Staphylococcus aureus - physiology / Th17 Cells - immunology / Training / Transcription / Tropical diseases / Vector-borne diseases