ATM1, an essential conserved transporter in Apicomplexa, bridges mitochondrial and cytosolic [Fe-S] biogenesis.

The Apicomplexa phylum encompasses numerous obligate intracellular parasites, some associated with severe implications for human health, including Plasmodium, Cryptosporidium, and Toxoplasma gondii. The iron-sulfur cluster [Fe-S] biogenesis ISC pathway, localized within the mitochondrion or mitosome of these parasites, is vital for parasite survival and development. Previous work on T. gondii and Plasmodium falciparum provided insights into the mechanisms of [Fe-S] biogenesis within this phylum, while the transporter linking mitochondria-generated [Fe-S] with the cytosolic [Fe-S] assembly (CIA) pathway remained elusive. This critical step is catalyzed by a well-conserved ABC transporter, termed ATM1 in yeast, ATM3 in plants and ABCB7 in mammals. Here, we identify and characterize this transporter in two clinically relevant Apicomplexa. We demonstrate that depletion of TgATM1 does not specifically impair mitochondrial metabolism. Instead, proteomic analyses reveal that TgATM1 expression levels inversely correlate with the abundance of proteins that participate in the transfer of [Fe-S] to cytosolic proteins at the outer mitochondrial membrane. Further insights into the role of TgATM1 are gained through functional complementation with the well-characterized yeast homolog. Biochemical characterization of PfATM1 confirms its role as a functional ABC transporter, modulated by oxidized glutathione (GSSG) and [4Fe-4S].

Pathogenic rickettsiae utilize the phosphatidylserine binding receptor CD300f on macrophages for host invasion and pathogenesis.

Some arthropod-borne obligate intracellular rickettsiae are among the most virulent human pathogens. Upon entry, Rickettsia species modulate immune (e.g., macrophages; MΦ) and non-immune cell (e.g., endothelial cells) responses to create a habitable environment for host colonization. In particular, MΦ play a crucial role in either terminating an infection at an early stage or succumbing to bacterial replication and colonization. However, our understanding on how Rickettsia species modulate crucial cellular processes within MΦ, including phagocytosis, and host cell defenses, to establish an intracytosolic replication niche, remain poorly defined. In this study, we describe a previously unappreciated mechanism, in which pathogenic rickettsiae infection is mediated by the phosphatidylserine (PS)-binding receptor, CD300f. We found that CD300f -/- mice but not wild-type (WT) C57BL/6J mice were protected against R. typhi - or R. rickettsii [ Shelia Smith ]-induced fatal rickettsiosis. Adoptative transfer studies further revealed that CD300f-expressing bone marrow-derived macrophages (BMDMΦ) are important mediators to control rickettsiosis in WT mice. Mechanistical analysis, using WT or CD300f -/- BMDMΦ, showed that CD300f facilitates the engulfment of both pathogenic R. typhi and R. rickettsii species, likely via a PS-mediated mechanism. Furthermore, CD300f was involved in the intracytosolic replication of both pathogenic rickettsiae by differentially modulating the anti-inflammatory Interleukin (IL)-10 and anti-rickettsial IL-1α and IL-1ß cytokine responses. Collectively, our findings describe a previously unappreciated role for the efferocytic receptor, CD300f, to facilitate engulfment and the intracellular survival of pathogenic rickettsiae within the host. Significance Statement: Vector-borne diseases, which are transmitted by hematophagous arthropods, like ticks and fleas, present a perilous threat to public health. In fact, tick- and flea-borne rickettsial diseases are on the rise globally and our current inadequate understanding on how Rickettsia interacts with their mammalian host has significantly impaired the development of effective interventions against pathogenic rickettsial infections. Here, we identified the phosphatidylserine (PS)-receptor, CD300f, as an important mediator of pathogenic rickettsiae infection in vivo and in vitro . Specifically, we showed that CD300f-expressing macrophages facilitate rickettsial infection by differentially modulating anti-inflammatory Interleukin (IL)-10 and anti-rickettsial IL-1α and IL-1ß cytokine responses. In sum, our data described CD300f as an important regulator of rickettsial infection and may present a target for therapeutic intervention.

Autophagy facilitates intracellular survival of pathogenic rickettsiae in macrophages via evasion of autophagosomal maturation and reduction of microbicidal pro-inflammatory IL-1 cytokine responses.

IMPORTANCE: Rickettsia spp. are intracellular bacterial parasites of a wide range of arthropod and vertebrate hosts. Some rickettsiae are responsible for several severe human diseases globally. One interesting feature of these pathogens is their ability to exploit host cytosolic defense responses to their benefits. However, the precise mechanism by which pathogenic Rickettsia spp. elude host defense responses remains unclear. Here, we observed that pathogenic Rickettsia typhi and Rickettsia rickettsii (Sheila Smith [SS]), but not non-pathogenic Rickettsia montanensis, become ubiquitinated and induce autophagy upon entry into macrophages. Moreover, unlike R. montanensis, R. typhi and R. rickettsii (SS) colocalized with LC3B but not with Lamp2 upon host cell entry. Finally, we observed that both R. typhi and R. rickettsii (SS), but not R. montanensis, reduce pro-inflammatory interleukin-1 (IL-1) responses, likely via an autophagy-mediated mechanism. In summary, we identified a previously unappreciated pathway by which both pathogenic R. typhi and R. rickettsii (SS) become ubiquitinated, induce autophagy, avoid autolysosomal destruction, and reduce microbicidal IL-1 cytokine responses to establish an intracytosolic niche in macrophages.

Panoramic Dominance of the Immune System in Cardiorenal Syndrome Type I.

Physiological organ cross-talk is necessary to maintain equilibrium and homeostasis. Heart and kidney are the essences of this equilibrium. Organ failure in either of these organs can perturb the bidirectional communication between them, impinging this unpleasant vascular and cellular milieu on other distant organs. Cardiorenal syndrome (CRS) type I occurs due to acute deterioration of cardiac function, ultimately causing acute kidney injury (AKI). This syndrome is an intricate condition with neurohormonal and inflammatory aspects. Inflammation creates a vicious circle filled with the innate and adaptive immune systems, pro-inflammatory cytokines, chemokines to actuate hemodynamic compromise in CRS type I patients. Pro-inflammatory cytokines not only aggravate fluid retention and venous congestion but also initiate apoptosis and oxidative stress. The immune response's primary motive is to elicit the heart and kidney to produce cytokines, intensifying the inflammatory process. Despite the possible standard of care, patient mortality, treatment cost, readmissions are extreme in CRS type I, and inflammation certainly has critical inferences warranting future research in humans.

The Role of Interleukin-6 and Inflammatory Cytokines in Pancreatic Cancer-Associated Depression.

Pancreatic cancer is historically known for representing a challenge for both diagnosis and treatment. Despite the advances in medicine, science, and technology, it remains the third leading cause of cancer-related deaths in the United States. The association between pancreatic cancer and major depression preceding the diagnosis is well known; however, it is still poorly understood, being considered an obscure piece of the puzzle the disease represents. It has been characterized as a paraneoplastic syndrome caused by the dysregulation of inflammatory cytokines, especially interleukin-6 (IL-6). Despite many types of studies describing the association, researchers have been reluctant to recommend it as a screening tool or early marker of the disease, mainly because of the non-specific nature of depression and anxiety in the studied patients. In this literature review, we aim to better understand the relationship between pancreatic cancer and major depression and characterize the immunologic mechanism of action behind the association.

[Fe-S] cluster assembly in the apicoplast and its indispensability in mosquito stages of the malaria parasite.

The relict plastid (apicoplast) of the malaria parasite is the site for important biochemical pathways and is essential for parasite survival. The sulfur mobilization (SUF) pathway of iron-sulfur [Fe-S] cluster assembly in the apicoplast of Plasmodium spp. is of interest due to its absence in the human host suggesting the possibility of antimalarial intervention through apicoplast [Fe-S] biogenesis. We report biochemical characterization of components of the Plasmodium falciparum apicoplast SUF pathway after the first step of SUF. In vitro interaction experiments and in vivo cross-linking showed that apicoplast-encoded PfSufB and apicoplast-targeted PfSufC and PfSufD formed a complex. The PfSufB-C2 -D complex could function as a scaffold to assemble [4Fe-4S] clusters in vitro and activity of the PfSufC ATPase was enhanced by PfSufD. Two carrier proteins, the NifU-like protein PfNfu and the A-type carrier PfSufA are homodimers, the former mediating transfer of [4Fe-4S] from the scaffold to a model [4Fe-4S] target protein with higher efficiency. Conditional knockout of SufS, the enzyme catalyzing the first step of SUF, by selective excision in the mosquito stages of Plasmodium berghei severely impaired development of sporozoites in oocysts establishing essentiality of the SUF machinery in the vector. Our results delineate steps of the complete apicoplast SUF pathway and demonstrate its critical role in the parasite life cycle.