Does infection with Leishmania protect against Covid-19?

The COVID-19 pandemic caused by the infection with the novel Coronavirus or the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) revealed individual and global vulnerabilities, affecting social, economic, political, and health system organization problems and which continues to affect all aspects of life worldwide [1]. In addition, COVID-19 infections have been responsible for stopping neglected tropical diseases (NTDs) control programs. The pandemic has significantly affected the advances in the fight against leishmaniasis, with its two forms, the visceral and cutaneous, impacting resource distribution and medication access [2]. Visceral leishmaniasis (VL) is a zoonosis caused by the protozoan L. infantum transmitted through the bite of hematophagous sandflies belonging to Phlebotomus. It may present general symptoms, including fever, malaise, and arthralgia, and may be indistinguishable from COVID-19 [3].VL is characterized by a CD4⁺ T response with the secretion of high levels of IFN-γ and IL-5 and has been associated with asymptomatic L. infantum infection [4]. Elevated levels of IFN-γ and IL-17 have also been observed during asymptomatic L. donovani infection [5]. During the active phase of VL, elevated levels of IFN-γ, TNF-α, IL-10, and IL-6 in plasma have been observed [6]. However, high levels of IFN-γ were similar to individuals cured of VL or asymptomatic infection [7]. Two cases of Leishmania-COVID-19 co-infection reported in the literature are described by Miotti et al. in an immunocompromised adult patient. The disease was associated with Leishmania persistence, which appears to be very common in patients with VL [8], impacting the innate and adaptive immune responses as evidenced by the inability of IFN-γ production by peripheral blood mononuclear cells stimulated with leishmanial antigens [9]. Until now, three cases of Leishmania-COVID-19 have been reported; the authors aim to draw attention to this issue and analyze the clinical characteristics of the co-infection [10]. Furthermore, Antonis Pikoulas suggest that Leishmania-COVID-19 co-infection may have led to the reactivation of previously asymptomatic leishmaniasis [11]. The relationships between VL and pandemic SARS-CoV-2 infection need to be further considered and investigated; both affected several organs.

The cutaneous leishmaniasis (CL) forms are the most prevalent, with an estimated 600 000 to 1 million new cases annually. This disease is responsible for significant psychosocial impacts due to the scars that persist after recovery [12]. A study conducted on participants with CL scar significantly reduced the incidence of COVID-19 morbidity and mortality [13]. The cross-protection mediated by CL may explain the retard COVID-19 in endemic countries and would significantly advantage developing countries, notably the Mediterranean region. In fact, a lower burden of COVID-19 incidence and case fatality during the pandemic has been documented in tropical and subtropical areas [14]. For CL, The clearance of Leishmania multiplication involved mainly cytotoxic CD8⁺ T cells and CD4⁺ helper T cells and the production of IFN-γ [15,16]. IFN-γ promotes parasite control by activating infected macrophages to produce leishmanicidal molecules such as nitric oxide (NO) capable of killing intracellular parasites, also one of the crucial cytokines for the defense against viruses. However, the early IFN responses are critical to controlling SARS-CoV-2; if it fails, the virus replicates in the lungs, enters the circulation, and leads to massive tissue destruction. During SARS-CoV-2 infection and in various patient studies, IFN-γ-producing T cell levels were higher [17]. Studies in patients have shown that the level of IFN-γ has increased in children with COVID-19, which has not been high compared to adults; this may explain why COVID-19 infection is not severe in children with the disease [18]. However, further studies are needed to explore the potential profile and duration of this protection offered by CL against COVID-19.

In addition, other types of parasitic NTDs can alter immunologic responses to COVID-19, representing a challenge for clinicians because of the current focus on pandemic management. Consequently, it could lead to inappropriate diagnoses and management of other life-threatening medical conditions, such as malaria. Malaria is also a parasitic disease caused by the genus Plasmodium and transmitted by Anopheles mosquitoes; it poses a significant global health threat displaying the greatest number of cases and the highest mortality [19]. Malaria and COVID-19 can share common symptoms, including fever, breathing difficulties, tiredness, and acute onset headache, which may lead to misdiagnosis of malaria for COVID-19 and vice versa [20,21]. They recently demonstrated that malaria-infected patients develop anti-GPI antibodies that could identify SARS-CoV-2 glycoproteins and play a protective role against COVID-19 or induce a milder disease pattern [21]. Also, interferons and neutralizing antibodies have been suggested to play roles in the low prevalence of COVID-19 in malaria-endemic countries.

With the rapid transmission of SARS-CoV-2, many people in endemic countries will be co-infected with SARS-CoV-2 and one or more of NTDs pathogens. Preexisting infection with any of these parasites may lead to changes in susceptibility and/or severity of COVID-19. Efforts are essential to understanding the potential impact of SARS-CoV-2 and some protozoal infections.