Recent findings show virus and bacterial infections can aggravate the skin and mucous membrane lesions caused by cutaneous leishmaniasis, a disease resulting from infection by a protozoan (a single-celled parasite) of the genus Leishmania. The presence of these pathogens in the body can increase the level of inflammation caused by the parasite and make it more difficult for the patient’s immune system to control.
Studies coordinated by Brazilian researchers over the last several years point in this direction, adding to scientists’ understanding of the mechanisms the protozoan uses to proliferate in the human body and create lesions that, when left untreated, can leave patients disfigured.
According to the Ministry of Health, there were approximately 13,000 confirmed cases and 12 deaths associated with cutaneous leishmaniasis disease in Brazil in 2022. More than 70% of the incidents were recorded in the North and Northeast regions. Cutaneous leishmaniasis is transmitted to humans through bites from female sandfly mosquitoes that are infected with the protozoan.
Brazilian immunologist Camila Farias Amorim, from the University of Pennsylvania, in the United States, published articles in 2019 and 2023 in the journal Science Translational Medicine showing that in attempting to defend themselves from the parasite, patients’ immune cells produce excessive quantities of a cytokine, interleukin-1 beta (IL-1β). This reaction increases skin ulceration and delays the healing process. Cytokines are small proteins that control the growth and activity of other cells in the immune system and blood. The researchers analyzed lesions from patients in the town of Corte de Pedra, in the Bahian municipality of Presidente Tancredo Neves.
In the studies, Amorim also reported finding colonies of Staphylococcus aureus in most of the lesions sampled. Commonly present on the skin, where it can lead to infection, this bacterium takes advantage of the open wounds caused by leishmaniasis to multiply, inducing excessive production of IL-1β and further delaying the healing process.
“In the United States, there are drugs approved for blocking the action of IL-1β in autoinflammatory diseases, such as some types of arthritis and gout,” says the immunologist. “We could test them on patients, in addition to adopting antibacterial therapies alongside antiparasitic treatment.”
For doctor Fernando Tobias Silveira, from the Evandro Chagas Institute, in Belém, Pará, scientific work on the role of bacteria in the severity of parasite infections already underlies a practice he adopts with his patients. “I always prescribe two series of an injectable antiparasitic medication made from pentavalent antimony compounds, with a topical medication, a combination of two antibiotics, neomycin and bacitracin, to help with wound healing,” says Silveira, who has been dedicated to treating patients with leishmaniasis for over 40 years.
Camila Farias Amorim / University of PennsylvaniaElectron microscopy image showing macrophages, a type of immune cell, which are infected by parasites of the genus LeishmaniaCamila Farias Amorim / University of Pennsylvania
Hacking the immune system
Two recent studies, coordinated by immunologist Dario Zamboni, from the Ribeirão Preto School of Medicine at the University of São Paulo (FMRP-USP), highlight the type of infectious agent that causes the Leishmania protozoan to alter the functioning of the inflammasome, a protein complex that triggers the inflammatory response. In research published in 2019 in the journal Nature Communications and 2021 in iScience, the São Paulo group shows that a virus that lives in symbiosis within the parasite tends to increase the levels of inflammation the disease causes.
This symbiotic virus is named Leishmania RNA Virus-1 (LRV-1). In laboratory analyses, samples of the Leishmania guyanensis parasite species—endemic to northern Brazil—were more likely to cause severe cases of the skin disease when contaminated by LRV-1. The elevated risk was due to the inhibition of caspase-11, one of the enzymes involved in regulating responses the inflammasome activates.
“Activation of the inflammatory process in the host is a double-edged sword. In many cases, it controls the infection and kills the parasite, as with asymptomatic patients,” explains Zamboni. “In some patients, who have a condition we don’t fully understand yet, the inflammation worsens the clinical picture and leads to the development of more serious lesions.”
Over the last two decades, several studies have demonstrated the protozoan load isn’t the sole factor that influences the severity of the disease; the way the body deals with the parasite is also involved. In an infection, the immune system’s macrophages engulf the parasite and, if it survives the attack, pyroptosis begins. In pyroptosis, the macrophage “commits suicide,” rupturing explosively and releasing inflammatory molecules that then start a new phase in the immunological battle.
However, in cutaneous leishmaniasis, this mechanism doesn’t always follow the expected script. In an article published in February last year in the journal Nature Communications, Zamboni’s team presented evidence that parasites of the genus Leishmania are capable of modulating the response of immune cells, delaying the death of macrophages and thereby prolonging parasite multiplication for a longer period within the host.
The researchers showed that in macrophages in humans and in lab mice, Leishmania can cause the gasdermin-D protein—important in macrophages’ pyroptosis process—to take on a modified structural form. The change is technically called “alternative cleavage of gasdermin-D,” meaning the parasite partially inactivates the protein and prevents it from carrying out its inflammatory functions properly.
The macrophages do release a certain dose of inflammatory cytokines, but not enough to cause cell death by pyroptosis, which is an essential step in the immune response. When this occurs, the protozoa can multiply to the point of bursting through the immune cells’ plasma membrane. They disperse throughout the body in search of more macrophages to infect and deceive.
Continued defeats of macrophages contribute to the immune system going into a tailspin, triggering attacks on healthy cells and uncontrolled inflammation. “The modulation of macrophage function can allow Leishmania to live in mammals for years, sometimes for the entire life of the infected individual,” observes the FMRP-USP researcher.
Project
Mechanisms and consequences of the activation of cytoplasmic receptors by intracellular pathogens (nº 19/11342-6); Grant Mechanism Thematic Project; Principal Investigator Dario Zamboni (USP); Investment R$5,580,498.81.
Scientific articles
CARVALHO, RVH et al. Endosymbiotic RNA virus inhibits Leishmania-induced caspase-11 activation. Iscience. Vol. 24, no. 1. Jan. 22, 2021.
CARVALHO, R. V. H. et al. Leishmania RNA virus exacerbates Leishmaniasis by subverting innate immunity via TLR3-mediated NLRP3 inflammasome inhibition. Nature Communications. Vol. 10, no. 1. Nov. 21, 2019.
AMORIM, C. F. et al. Variable gene expression and parasite load predict treatment outcome in cutaneous leishmaniasis. Science Translational Medicine. Vol. 11, no. 519. Nov. 20, 2019.
