Research Reveals How Virus Makes Leishmaniasis More Severe

In orange we see leishmania infecting a macrophage, one of the first defense cells to come into action during an infection

A research developed by the Immunologist Dr. Renan Villanova Homem de Carvalho, at the School of Medicine of Ribeirão Preto, University of São Paulo (FMRP-USP), entitled “Endosymbiotic RNA virus inhibits Leishmania-induced caspase-11 activation”, published in the scientific journal iScience  reinforces the idea of that the leishmania RNA virus (LRV) exacerbates leishmaniasis, contributing to the appearance of the mucocutaneous form, which is more severe than its conventional form, the cutaneous.

According to the study, which was held at the laboratory managed by Dr. Dario S. Zamboni, professor at FMRP/USP, LRV inhibits the activation of caspase-11, a protein that is part of the defense system of mammalian cells (including humans), through virus-stimulated autophagy. “In previous studies by our laboratory (de Carvalho et al, Cell Reports, 2019; de Carvalho et al, J Leuko Bio, 2019) and others (Chaves et al, Plos Path, 2019), caspase activation was demonstrated -11 by leishmania induces non-conventional/non-canonical inflammasome activation of NLRP3, a cytosolic molecular platform that controls parasite replication. In the present study, we demonstrated that LRV inhibits the activation of caspase-11 by the parasite”, explains Dr. de Carvalho, currently researcher at the Lymphocytes Dynamics Laboratory, at Rockefeller University, NY. In other words, LRV helps with a dribble in our immune system so that leishmania survives inside our cells.

The NLRP3 protein has been described by several research groups, including Dr. de Carvalho, as an important factor involved in the development of leishmaniasis. “Caspase-11 is an enzyme directly involved in NLRP3, activation, but this had only been described in the context of bacterial infections. What is new is that we describe the activation of caspase-11 and, consequently, NLRP3, also by parasites (published in previous works). Further, we demonstrated in this work that LRV manipulates caspase-11 to favor parasitic growth, details Dr. de Carvalho

According to another pioneering study published by the group (de Carvalho et al, Nat Commun, 2019), when LRV-infected leishmania enters the body, the virus activates a receptor on cells called TLR3, causing the immune system to produce the type 1 interferon substance. Interferon, in turn, induces autophagy in human cells, that is, a process of degradation and recycling of cell components. Once inside the macrophages, the main cell inhabited by the parasite, in which it establishes its replicative niche, the virus manages to modulate several receptors. The action culminates in the inhibition of two key molecules, such as NLRP3 and ASC, which are crucial for disease control.

Contribution to drugs and diagnosis

Leishmaniasis is considered endemic in some regions of the country. According to the Ministry of Health, in Brazil, around 21 thousand cases of tegumentary leishmaniasis are registered annually, which includes cutaneous and mucocutaneous. The North region has the highest number of cases, followed by the Midwest and Northeast regions. The mucocutaneous type, caused by species of New World leishmania, such as L. guyanensis and L. braziliensis, causes localized lesions on the skin and, in more severe cases, when there is dissemination of wounds, the lesions also start to appear in the mucous membranes, often in the nose, mouth and throat, which can disfigure the patients face and become lethal.

When leishmania infects people, it wants to survive while our immune system tries to eliminate the parasite. However, when leishmania has the virus, it shuts down those mechanisms in our immune system that fight the parasite. As the protein that kills leishmania is being silenced by the virus, leishmania is able to survive, proliferate and cause mucocutaneous leishmaniasis. Several factors, related to the host and the parasite, contribute to the clinical evolution of each patient, and studies show that LRV is a crucial factor in increasing the probability of developing mucocutaneous disease, although not all patients are infected with carrier parasites virus develop clinical outcome.

“In our articles, we have always argued that every patient diagnosed with leishmaniasis should also undergo molecular analysis to see if leishmania has the virus. If the presence of LRV is confirmed, the ideal would be topical treatment with a TLR3, antagonist/blocker, a key receptor involved in the signaling cascade triggered by the virus that induces Caspase-11/NLRP3, blockade, which may culminate in the patients clinical worsening. In this way, the chance of the patient remaining in the cutaneous form, which has more effective treatment and tends to self-heal over time, would increase”, he alerts.

Treatments for leishmaniasis remain the same as decades ago, with few advances in this regard over the last few years, despite significant progress in understanding the host-pathogen interaction. Other recent works, in line with the findings of Dr. de Carvalho, have demonstrated the activation of non-canonical caspases (such as caspase-11) in other models of parasitic infection, such as toxoplasmosis. This means that their findings have had an impact on understanding the host-microorganism relationship with other diseases as well, and on advancing the understanding of the signaling pathways of the innate immune response in general. Perhaps the next few years may reserve new strategies for both the diagnosis and the treatment of leishmaniasis and other tropical diseases.

Brazilian research determination

“All the studies mentioned were carried out exclusively in Brazil, with the strength and resilience of Brazilian researchers, often working in non-ideal situations, far below the gold standard of science carried out in other countries. However, our works were extremely awarded in Brazil and abroad, being published in the best international journals. I am immensely proud not only of the researchers who worked with me in carrying out these researches, but of all Brazilian scientists who resist and continue to do quality science in the country, despite all current government public policies that undermine, discourage, frustrate and slow down the Brazilian scientific progress. I have complete confidence that these researchers, who are strong and determined, will overcome denial and all retaliation to put the country back on the path of development and on the right path in history”, he concludes.

Watch here the video in which Dr. de Carvalho talks about the discovery of the virus.