Trypanosoma Cruzi Experimental Infection and COVID-19: Similar Cardiovascular Syndrome?

Introduction

Chagas disease

Trypanosoma Infection: Dr. Carlos Chagas, in 1909, published his notable discovery, a new pathology denominated Chagas disease [1]. An unprecedented medicine feat, he was able to identify: etiologic agent, the protozoan Trypanosoma cruzi, its biological cycle and your pathogenesis [2]. This disease affects a large part of the world population in a situation of social vulnerability, considered a neglected disease (NTDs) [3]. Actions to control the endemic infection of T. cruzi were perform, such as the eradication of its invertebrate vector (by Triatoma infestans) and required testing in blood donnors [4-6]. As described by Moncayo & Silveira (2009) the Latin Amerca incidence of Chagas disease has dropped from 700.00 to 40.000 new cases per year [6]. Death number per year is between 45.000 to 12.500 patients deaths6. The main route of transmission is still vector through the bite of insects popularly called “Barbeiro”, “Chupança” or “Vinhuca”. However, its infectious form, the metacyclic trypomastigote, can be found in natural foods, such as açaí, bacaba and fruit pulps, increasing its risk of transmission through oral contamination [7,8]. The classic pathogenesis has two distinct phases: the acute phase, characterized by mild, non-specific symptoms [6-8], in which approximately 10% of all patients have severe myocarditis, with 90% of these having an unfavorable prognosis [9]. Approximately 20 to 30% of infected patients will develop the symptomatic chronic phase, which is the most severe, with severe cardiac involvement due to chronic myocardiopathy and the presence of dilations in digestive organs, such as the megaesophagus and megacolon [3,10]. According Lizzeti et, al., (2019) he only drugs available for the treatment of T. cruzi infection are nifurtimox and benznidazole [10]. However, currently benznidazole is the most widely used drug, however it is not effective during the chronic symptomatic phase of the disease and can promote serious side effects, especially in infants [10,11]. Moreover, to date, no other drug has had a trypanocidal efficacy similar to benznidazole and we still do not have a vaccine, despite more than 100 years of disease research [11-13].

The experimental mouse model, depending on the binomial of infection, mouse lineage & parasite strain becomes more susceptible or resistant to infection14. However, it allows the investigation of several aspects of the pathogenesis of T. cruzi infection in a relatively short period of time. In addition, due to its genetic homology to the human being, several approaches can be clarified, such as immunological response, cardiac remodeling and preclinical tests for the evaluation of experimental chemotherapies in the search for an effective compound for the treatment of chagasic patients [14,15].

Severe Acute Respiratory Syndrome Coronavirus-2

COVID-19:

In accordance with the excellent review by Youki et al. [16] during 2019, a new Severe Acute Respiratory Syndrome, promoted by a member of the Coronavirus family, emerged in Wuhan (China province), whose origin has not yet been totally elucidate, probably zoonotic way transmission. SARS-Cov-2 or COVID-19 is characterize by high transmissibility and high morbidity. Thus, in 2020 it became a global pandemic, after virus modifications, was observed humanhuman infection [16-18].

The classic symptoms of COVID-19 are characterized by the involvement of the respiratory system, from asymptomatic to severe cases19. There is fever, dry and prolonged cough, difficulty breathing and pneumonia [19-21]. However, the mechanism of infection of the virus in the body occurs through an enzyme called angiotensin-converting enzyme type 2, or ACE2 (the spike for COVID-19 also bound to ACE2), present in lung tissue [21-22]. However, ACE2 is also found in several other tissues, mainly the endothelium of the lung, heart, ileum, kidney and bladder [22,23]. Thus, it is currently believed that the evolution of respiratory cases to death due to cardiovascular shock caused by thromboembolism is associated with the connection between COVID-19 and endothelial ACE2 expression, however it is still not completely elucidated, but probably occurs microvascular compromise [24,25]. The prognosis may be even more unfavorable, because in some patients, this virus can also affect the central nervous system (CNS) [24,26].

State-of-Art

The preclinical study of T. cruzi infection, since 1909, demonstrated a diverse use of biomodels, such as mice, rats, dogs and opossums [25]. However, with the refinement of techniques and the use of transgenic models using the mouse model, it became possible, especially in Outbred Stock mice, to evaluate, in a short period of time, the evolution of the acute phase, the symptoms in the chronic phase and the effectiveness of experimental compounds, more closely the possibility of translating the results to the patient with reliability [17]. However, experimental murine infection, in the acute and chronic phase, has always had a primary focus on cardiac involvement and the, still unknown, mechanism to which asymptomatic patients develop Chagas’ heart disease [27]. Experimental infection by COVID-19 still requires unconventional models in the science of laboratory animals, such as ferrets and humanized mice Taconic and Jackson Labs developed: Tbd, expressing human ACE2; Ace2 knockout, ACE2 Low expression and K18-hACE2- ACE2 expression; Tmprss2 Knockout; Stat1 knockout. Standards murine lineages as Balbc, C57Bl6 agedependent develop clinical illnesses, including irregular interstitial pneumonia [28]. The conception of this review was based on the hypothesis of possible similarities between the use and evaluation of the experimental mouse biomodel in both infections, both by the parasite and the viral. We are convinced that, among striking differences, the use of the mouse biomodel in both infections is not contemplating the elements of the complex network associated between the various biological systems, such as only the cardiac involvement in T. cruzi infection and the involvement of the lung in the case of COVID-19.

Compilation and Reflections

According to Yuki et. Al. [16] the severity criteria for COVID-19 infection are determined by

1. Asymptomatic COVID: Without any clinical symptoms imaging diagnosis normal.
2. Mild Acute: Uupper respiratory tract syntomd as: fever, fatigue, myalgia, cough, sore throat, runny nose, sneezing or digestive symptoms.
3. Moderate Respiratory: with fever, cough, hypoxemia and imaging chest test positive.
4. Severe Respiratory: severe hypoxemia
5. Systemic complications: severe pneumonia, heart failure, cardiovascular shock; encephalopathy and acute kidney injury [16].

In the experimental study of acute T. cruzi infection in mice one of the most susceptible binomials is the Balbc lineage & Y strain infection. It promotes high mortality due to the severity of acute myocarditis and is a widely used model for assessing the immune response. Our research group demonstrated that before the evolution of acute myocarditis there is, even during the presence of parasites in the blood, a marked, but transient, acute kidney injury [29,30]. We evaluated, in vitro, the several types infection of renal cells infected by T. cruzi and observed that there was an inverse relationship, mainly in mesangial cells, that the presence of the parasite, not necessarily replicating in renal tissue, increased the oxide nitric levels in the cell culture supernatant, as well as cytokine TNF [30]. At the cellular level, this may be one of the explanations for the early acute kidney injury and its consequences, such as the drop in blood pressure and the perception of the justaglomerular apparatus (immunocomplex deposition) [31], activating the reninangiotensin- aldosterone system (RAAS).

The activated RAAS can perform several systemic effects, such as vasoconstriction, in this case, as a positive feedback to the perception of a decreased in cardiovascular pressure, endothelial and cardiac muscle remodeling [32]. Our in vivo investigation has shown that the use of multi-stage RAAS blockers (losartan, captopril and spironolactone), directly interfere in increasing the animals’ survival, which suggests that not only is acute myocarditis the cause of death of the animals, but rather the influence of the renal-cardio axis associated with the severity of the acute inflammatory response in the heart muscle [33]. Interestingly, the use of spironolactone significantly minimized the mortality of mice infected with T. cruzi [33]. Our theory, still in studies, would be that the parasite, inside the organism, promotes some type of toxicity, ancient manuscripts describe the possibility of chagastoxin [34,35]. Thus, we would have an association between acute kidney injury, histopathological analysis showed glomerular IgM deposits [29], changes in the cardiovascular and endothelial system, myocardial inflammatory response due to parasitic multiplication, evolution to cardiogenic shock and death of the animal [36]. Spironolactone suggests minimizing the effects of this possible parasite endo or exotoxin, decreased vasodilation, or loss of elasticity of the endothelium, balancing blood pressure in the vessels and avoiding cardiogenic shock [37,38]. Melnikov et al. [39] described that, during different phases, T. cruzi infection can be observed in lungs. The parasite presence were were accompanied by mononuclear inflammatory infiltrate promoted compromised in the alveoli walls and lung hemorrhage [39,40].

Ingraham et al. [41] suggest RAAS inhibition decreases COVID-19 lung injury and improves survival, while simultaneously decreasing viral load in animal models with viral infections that utilize the ACE2 receptor [38]. Experimental acute T. cruzi infection, showed that RAAS-block throught use (before infection) of multistage RAAS blockers (losartan, captopril and spironolactone), directly interfere in increasing the animals’ survival, which suggests that not only is acute myocarditis the cause of death of the animals, but rather the influence of the renal-cardio axis associated with the severity of the acute inflammatory response in the heart muscle [33]. So, when we compare both infections and the serious stage of COVID-19, it suggests that the key mechanism we should be looking at would be the modulation of the RAAS. Mainly using an initial system blocker such as Aliskiren that blocks Renin’s conversion [41].

Conclusions

In this review, we do not intend to compare or suggest translate of the infection and the relationship between the evolution and severity of COVID-19 with the experimental T. cruzi infection. Our goal is for our observation and knowledge of both infections, and the long experience in the development of the science of laboratory animals, to propose key points that can be used by other research groups in the search for the mitigation of this terrible pandemic and in some way, we are prepared for others broad-spectrum viral, bacterial, parasitic infections that could become a global public health problem [42].

We believe, in addition to physical structures, personal training and an increase in the technological and scientific political development, that at the laboratory level, using animals for scientific purposes, some chalenges are important at this moment:

1. Development of a murine model, a mouse biomodel, capable of developing in house facilities the COVID-19 infection in a similar way to critically ill patients.
2. Refine biomodel assessment techniques, primarily by using equipment that enables the assessment of environmental and controlled transmissibility of the virus, not only susceptibility to intranasal inoculations.
3. Use techniques and procedures that are closest to those used by humans, especially at the critical and systemic level of infection, such as endothelial changes, thromboembolism and pulmonary embolism.
4. Possibility of quickly, reproducibly and reliably testing experimental therapies, acute and chronic toxicity of new compounds (or repositioning of drugs) and vaccines.

Finally, we would like to affirm that the identification of kidney injury in mice infected with T. cruzi during the acute phase was relevant because, in many moments, we “close” the focus on an organ or system and as the infection by COVID-19, we must observe the genesis of the pathology in a complex interconnected system, because in both cases, the infection will progress to cardiovascular shock and multiple organ failure.

Sharing one of our hypotheses, we believe that, as already observed, patients infected in the acute phase are also presenting with acute kidney injury. Would there be a possibility that the cardio-renal axis is involved in 20 to 30% of the population that has severe cardiac symptoms in the chronic phase of Chagas disease? So, research on the cardiovascular system in critically ill patients infected with COVID-19, can be a field of study, primarily to save the lives of these patients, but used to increase knowledge of the genesis of cardiovascular syndromes, such as thrombosis, strokes and others.

Epigenetic Regulation of Long non-coding RNAs on the ECM in pPROM

Long non-coding RNAs (lncRNAs) are long single-stranded RNAs with no translational potential. LncRNAs function in regulating epigenetic and cellular processes through various mechanisms. By analyzing the present available studies of lncRNA transcripts within the reproductive system and the current understanding of the biology of lncRNAs, the important diagnostic and therapeutic roles of lncRNAs in the etiology of reproductive disorders have been illustrated [100]. LncRNA is a mediator of the outcomes of interaction at the maternal–fetal interface and in the biological mechanisms underlying trophoblast differentiation [101,102]. In addition to miscarriage, intrauterine grown retardation, preeclampsia, and gestational diabetes mellitus [103,104], a pathogenic role for lncRNA has been observed in human sPTB, wherein the epigenetic regulatory function of lncRNA was found to link social and environmental exposures and the outcome of pregnancy [105,106]. Down-regulation of lncRNAs on laminin, collagens, VLAα10, OPN, α6β1, and α/βDG, which also implied that these lncRNAs may be significant for the decreased synthesis of mRNA and leaded to weakening of the ECM. Several co-differentially expressed pairs of lncRNA–mRNA sharing the same genomic loci in sPTB were recognized as being associated with the infectioninflammation pathway and ubiquitine-proteasome system [107].

Conclusion

The above experimental and clinical data have identified the causal nature of intrauterine infection and cervix vaginal infection in explaining the progress of sPTB and pPROM. The inflammatory response can lead to the activation of mechanisms and resulting in labour. But in some cases, pregnancy with the infection can maintain to term without complications. In other cases, the major event is activation of myometrial movement, leading to the risk of sPTB. In other cases, the primary outcome is the secretion of MMP from fetal membranes, resulting in pPROM. Therefore, a better understanding of the relationship between the ECM and the pPROM remains limited and is elucidated to shed light on effective strategies to provide opportunities to prevent the potential risk of pPROM during pregnancy.

Conflict of Interest

No conflict of interest declared.

Acknowledgement

This study is supported in part by the New York State Research Foundation for Mental Hygiene (914-3280, 914-3257), and the National Institutes of Health (R01 HD094381)..

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