Introduction
Toxoplasma gondii as an intracellular parasite can infect approximately one-third of the residents worldwide [
1]. Nearly, 39.3% of the population of Iran and 35.1-41% of people in the Northwest Iran are infected with toxoplasmosis [
2,
3]. Latent toxoplasmosis has long been considered asymptomatic in immunocompetent people, but it can result in serious or life-threatening disease in patients with haematologic malignancy, immunocompromised cancer patients, organ transplants and pregnant women [
1,
4‐
6]. Toxoplasmosis is also associated with various autoimmune [
7] and inflammatory diseases [
8] as well as some cancers [
9,
10].
The first cases of coronavirus disease 19 (COVID-19) with an unknown source were reported in Wuhan, China [
11]. SARS-CoV-2 has been shown to impair immune responses and uncontrolled inflammatory responses “cytokine storm” in severe and critical patients with COVID-19. Based on the clinical presentation (from asymptomatic to severe) of mixed infections of COVID-19 with other pathogens, including influenza A [
12],
Streptococcus pneumoniae [
13] fungal [
14] and
T. gondii [
15], indicating these infections could increase the severity of COVID-19. The co-occurrence of COVID-19 and toxoplasmosis as emerging intracellular infections in immunosuppressed individuals may lead to a higher incidence of mental and physical health problems [
15‐
17].
Conflicting results regarding the association between
T. gondii and COVID-19 have been discussed by several researchers. Some evidence also suggests that COVID-19 can reactivate latent
T. gondii [
18,
19]. However, other researchers claim that latent
T. gondii infection can trigger suppressor effects and reduce the severity of COVID-19 through overexpression of interferons (I and II) [
20,
21]. Therefore, due to the potential impact of toxoplasmosis on COVID-19 mortality, further studies are needed to clarify these apparent contradictions.
In terms of clinical significance,
T. gondii infection can progress from the latent phase to the active phase through a decrease in CD8
+ and CD4
+ cells, which may lead to dangerous complications in COVID-19 patients [
15,
22]. The possible association between latent toxoplasmosis and COVID-19 patients has been characterized worldwide [
16,
20,
21,
23]. However, there is no case-control study on the genetic diversity of
Toxoplasma co-infection in Iranian COVID-19 patients. The current investigation aimed to examine the probable association between toxoplasmosis and COVID-19 using serological and molecular methods in northwest Iran.
Discussion
Bi-functional effects in the relationship between
T. gondii and COVID-19 patients have been stated by several studies [
18‐
21]. Current results showed a relatively high seroprevalence of anti-
Toxoplasma IgG antibody (35.7%) among the COVID-19 patients in Tabriz; however, no meaningful association was observed between
Toxoplasma seropositivity in COVID‑19 patients compared to healthy subjects.
A study reported that overall mortality in moderate or severe COVID-19 disease was associated with a positive anti-
Toxoplasma’s IgG titer in Mazandaran, Northern Iran. However, no significant association was found between
T. gondii infection and COVID-19 severity [
17]. Geraili et al. (2022) have also shown that acute and latent toxoplasmosis infections circulate among COVID-19 patients in Golestan Province, Northern Iran. Furthermore, the prevalence of anti-
T. gondii IgM and IgG antibodies were 5.0% and 26.1%, respectively, in COVID-19 patients. However, no significant associations have been found between
T. gondii infection and COVID-19 severity [
28].
On the other hand, Sharaf-El-Deen (2021) showed that toxoplasmosis through over-expression of lymphocytic PD-1 can be considered an independent risk factor for the severity of COVID-19 [
15]. Roe (2021) pointed out that SARS-CoV-2 in synergy with active toxoplasmosis, intensifies the clinical symptoms in COVID-19 patients and leads to a challenging public health concern in all around the world [
29].
Roe (2021) reported the association between
T. gondii infection and higher mortality in COVID-19 patients with schizophrenia in Germany [
30]. Nevertheless, another study did not confirm a strong association between
T. gondii infection and susceptibility to COVID‑19 [
21]. In a recent study in the Mexican population, the prevalence of IgG and IgM anti
-Toxoplasma antibodies was demonstrated in 27.34% and 13.6% of COVID-19 patients, respectively [
31]. A study conducted on the Czech and Slovak populations showed that toxoplasmosis is not considered a risk factor for COVID-19 and
Toxoplasma-infected patients [
16].
The current results showed that risk factors such as close contact with stray cats and consumption of raw vegetables can increase the transmission of T. gondii infection to COVID-19 patients. Hence, educational policies such as thoroughly washing contaminated vegetables to remove oocysts and feeding cooked food to stray cats should be applied to COVID-19 patients with toxoplasmosis.
In this study, despite the low number of CD4
+T cells, no severe clinical symptoms of active toxoplasmosis (lymphadenopathy, chorioretinitis and cerebral/pulmonary manifestations) were detected in COVID-19 patients infected with high titer of
T. gondii IgG. However, Erol et al. (2022) reported secondary toxoplasmosis chorioretinitis with retinal detachment that developed shortly after COVID-19 infection [
23].
T. gondii can cause latent toxoplasmosis in the brain, central nervous system (CNS) and muscles [
32]. TH1-associated pro-inflammatory cytokines (cell-mediated immunity) are the main immunity responses against
T. gondii infection [
33]. According to this fact, a chronic inflammatory response against toxoplasmosis could exacerbate the severity of COVID-19.
Recent evidence shows that CD4 T cell and CD8 T cell depletion occurs during co-infection of coronavirus disease and toxoplasmosis, called “polyspecific T cell exhaustion” leading to overproduction of TH2 cytokines [
34]. Subsequently, switching the TH1 response to TH2 could reactivate latent toxoplasmosis in COVID-19 patients.
CD4 T cell depletion increases CD8 T cell depletion because the lack of interleukin-21 signals secreted by CD4 T cells directly increases CD8 T cell depletion [
35]. Consequently, loss of CD4 T cell functions due to CD4 T cell depletion leads to a reduction in interferon-γ levels, a crucial cytokine required to control both chronic and acute toxoplasmosis [
34]. On the other hand, Lucas et al. (2020) demonstrated that helminths can alter the severity of COVID-19. Indeed, during helminth infections, host immune responses shift toward TH2 polarization with a controlled inflammatory component that reduces mortality/morbidity in COVID-19 patients [
36].
In this study, high genetic diversity of T. gondii GRA6 sequences (including five codon substitutions) was found in COVID-19 patients. The emergence of haplotype diversity in latent toxoplasmosis should be considered in view of the emergence of treatment-resistant alleles and/or the development of pathogenesis, particularly in symptomatic COVID-19 patients with high disease severity.
In this study, we were unable to determine the level of T. gondii genetic diversity in COVID-19 patients infected with high titer of T. gondii IgM antibody. Furthermore, we could not authentically compare the haplotype substitutions of the GRA6 sequences of T. gondii between latent and active toxoplasmosis. One of the limitations of the present study was that the number of T. gondii sequences obtained from COVID-19 patients was small to infer large-scale genetic diversity.
The present study revealed that T. gondii type I infections are unequivocally circulating among COVID-19 patients in Tabriz, Northwest Iran. This study found an insignificant correlation between Toxoplasma infection and COVID-19 patients. The detection of T. gondii in COVID-19 patients will help to develop an epidemiological understanding of toxoplasmosis and implement preventive programs in the region. To make more accurate health decisions, multicenter investigations with a larger sample size of different ethnic groups of the Iranian population are needed.
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