Toxoplasma gondii is a prevalent parasite of medical and veterinary importance. Tachyzoïtes and bradyzoïtes are responsible for acute and chronic toxoplasmosis (AT and CT), respectively. In immunocompetent hosts, AT evolves into a persistent CT, which can reactivate in immunocompromised patients with dire consequences. Imiquimod is an efficient immunomodulatory drug against certain viral and parasitic infections. In vivo, treatment with Imiquimod, throughout AT, reduces the number of brain cysts while rendering the remaining cysts un-infectious. Post-establishment of CT, Imiquimod significantly reduces the number of brain cysts, leading to a delay or abortion of reactivation. At the molecular level, Imiquimod upregulates the expression of Toll-like receptors 7, 11, and 12, following interconversion from bradyzoïtes to tachyzoïtes. Consequently, MyD88 pathway is activated, resulting in the induction of the immune response to control reactivated Toxoplasma foci. This study positions Imiquimod as a potent drug against toxoplasmosis and elucidates its mechanism of action particularly against chronic toxoplasmosis, which is the most prevalent form of the disease.

The succinate receptor, SUCNR1, has been attributed to tumor progression, metastasis, and immune response modulation upon its activation via the oncometabolite succinate. Nonetheless, little is known about the prognostic relevance of SUCNR1 and its association with tumor immune infiltrates and microbiota in renal cell carcinoma (RCC). Herein, publicly available platforms including Human Protein Atlas, cBioPortal, TIMER2.0, and TISIDB were utilized to depict a divergent implication of SUCNR1 in the immune microenvironment of clear cell RCC (KIRC) and papillary RCC (KIRP); the two major subtypes of RCC. Our results showed that the SUCNR1 expression level was augmented in RCC compared to other solid cancers, yet with opposite survival rate predictions in RCC subtypes. Consequently, a higher expression level of SUCNR1 was associated with a good disease-specific survival rate (p = 5.797 × 10⁻⁵) in KIRC patients albeit a poor prognostic prediction in KIRP patients (p = 1.9282 × 10⁻³). Intriguingly, SUCNR1 was mainly correlated to immunomodulators and diverse immune infiltrates in KIRP. Additionally, the SUCNR1 was mostly associated with a repertoire of microbes including beneficial bacteria that likely influenced a better disease-specific survival rate in KIRC. Our findings illustrate a significant novel subtype-specific role of SUCNR1 in RCC which potentially modulates tumor immune infiltration and microbiome signature, hence altering the prognosis of cancer patients.

Cutaneous Leishmaniasis (CL) is a neglected tropical disease, classified by the World Health Organization (WHO) as one of the most unrestrained diseases. The Syrian war and the significant displacement of refugees aggravated the spread of this ailment into several neighboring countries in the Eastern Mediterranean Region (EMR). In Syria, Leishmania tropica is identified as one of the most aggressive and endemic identified species, causing localized or generalized lesions, often chronic or relapsing. Pentavalent antimonial drugs are currently used as first line treatment against CL. Nonetheless, these drugs exhibit several limitations, including the repetitive painful injections, high cost, poor availability, and mainly systemic toxicity. Besides, the emergence of acquired parasitic resistance hinders their potency, stressing the need for new therapies to combat CL. Natural products (NPs) epitomize a valuable source in drug discovery. NPs are secondary metabolites (SMs) produced by plants, sponges, or a wide variety of organisms, including environmental microorganisms. The EMR is characterized by its immense biodiversity, yet it remains a relatively untapped area in drug discovery. NPs of the region were explored over the last 2 decades, but their discoveries lack biogeographical diversity and are limited to the Red Sea. Here, we isolated previously uncultured environmental soil-dwelling Streptomyces sp. HAS1, from Hasbaya region in southeast Lebanon. When fermented in one of our production media named INA, HAS1 produced a crude extract with significant potency against a clinical Leishmania tropica isolate. Using bio-guided fractionation, the bioactive compound was purified and the structure was elucidated by NMR and LC-HRMS. Our findings establish NPs as strong candidates for treating Leishmania tropica and further dwells on the importance of these natural sources to combat microbial infections.

Toxoplasmosis is a prevalent parasitic disease caused byToxoplasma gondii(T. gondii). Under the control of the host immune system,T. gondiipersists as latent bradyzoite cysts. Immunosuppression leads to their reactivation, a potentially life-threatening condition. Interferon-gamma (IFN-γ) controls the different stages of toxoplasmosis. Here, we addressed the role of the parasite surface antigen P18, belonging to the Surface-Antigen 1 (SAG-1) Related Sequence (SRS) family, in a cyst-forming strain. Deletion ofP18gene (KOP18) impaired the invasion of parasites in macrophages and IFN-γ-mediated activation of macrophages further reduced the invasion capacity of this KO, as compared to WT strain. Mice infected by KOP18, showed a marked decrease in virulence during acute toxoplasmosis. This was consequent to less parasitemia, accompanied by a substantial recruitment of dendritic cells, macrophages and natural killer cells (NK). Furthermore, KOP18resulted in a higher number of bradyzoite cysts, and a stronger inflammatory response. A prolonged survival of mice was observed upon immunosuppression of KOP18infected BALB/c mice or upon oral infection of Severe Combined Immunodeficiency (SCID) mice, with intact macrophages and natural killer (NK) cells. In stark contrast, oral infection of NSG (NOD/Shi-scid/IL-2Rγnull) mice, defective in macrophages and NK cells, withKO P18, was as lethal as that of the control strain showing that the conversion from bradyzoites to tachyzoites is intact and, suggesting a role of P18 in the response to host IFN-γ. Collectively, these data demonstrate a role for P18 surface antigen in the invasion of macrophages and in the virulence of the parasite, during acute and chronic toxoplasmosis.

The succinate receptor, SUCNR1, has been attributed to tumor progression, metastasis, and im-mune response modulation upon its activation via the oncometabolite succinate. Nonetheless, lit-tle is known about SUCNR1 prognostic relevance and its association with tumor immune infil-trates and microbiota in renal cell carcinoma (RCC). Herein, publicly available platforms in-cluding Human Protein Atlas, cBioPortal, TIMER2, and TISIDB were utilized to depict a diver-gent implication of SUCNR1 in the immune microenvironment of clear cell RCC (KIRC) and pa-pillary RCC (KIRP); the two major subtypes of RCC. Our results showed that SUCNR1 expression level was augmented in RCC compared to other solid cancers, yet with opposite survival rate predictions in RCC subtypes. Consequently, higher expression level of SUCNR1 was associated with a good disease-specific survival rate (p=5.797e-5) in KIRC patients albeit a poor prognostic prediction in KIRP patients (p=1.9282e-3). Intriguingly, SUCNR1 was mainly correlated to im-munomodulators and diverse immune infiltrates in KIRP. Whereas the receptor was mostly asso-ciated with a repertoire of microbes including beneficial bacteria that likely influenced a better disease-specific survival rate in KIRC. Our findings illustrate a significant subtype-specific role of SUCNR1 in RCC which potentially modulates tumor immune infiltration and microbiome sig-nature, hence altering the prognosis of cancer patients.