HIF-α Activation Impacts Macrophage Function during Murine Leishmania major Infection

Leishmanial skin lesions are characterized by inflammatory hypoxia alongside the activation of hypoxia-inducible factors, HIF-1α and HIF-2α, and subsequent expression of the HIF-α target VEGF-A during Leishmania major infection. However, the factors responsible for HIF-α activation are not known. We hypothesize that hypoxia and proinflammatory stimuli contribute to HIF-α activation during infection. RNA-Seq of leishmanial lesions revealed that transcripts associated with HIF-1α signaling were induced. To determine whether hypoxia contributes to HIF-α activation, we followed the fate of myeloid cells infiltrating from the blood and into hypoxic lesions. Recruited myeloid cells experienced hypoxia when they entered inflamed lesions, and the length of time in lesions increased their hypoxic signature. To determine whether proinflammatory stimuli in the inflamed tissue can also influence HIF-α activation, we subjected macrophages to various proinflammatory stimuli and measured VEGF-A. While parasites alone did not induce VEGF-A, and proinflammatory stimuli only modestly induced VEGF-A, HIF-α stabilization increased VEGF-A during infection. HIF-α stabilization did not impact parasite entry, growth, or killing. Conversely, the absence of ARNT/HIF-α signaling enhanced parasite internalization. Altogether, these findings suggest that HIF-α is active during infection, and while macrophage HIF-α activation promotes lymphatic remodeling through VEGF-A production, HIF-α activation does not impact parasite internalization or control.

Phlebotomus papatasi Antimicrobial Peptides in Larvae and Females and a Gut-Specific Defensin Upregulated by Leishmania major Infection

Phlebotomus papatasi is the vector of Leishmania major, causing cutaneous leishmaniasis in the Old World. We investigated whether P. papatasi immunity genes were expressed toward L. major, commensal gut microbes, or a combination of both. We focused on sand fly transcription factors dorsal and relish and antimicrobial peptides (AMPs) attacin and defensin and assessed their relative gene expression by qPCR. Sand fly larvae were fed food with different bacterial loads. Relish and AMPs gene expressions were higher in L3 and early L4 larval instars, while bacteria 16S rRNA increased in late L4 larval instar, all fed rich-microbe food compared to the control group fed autoclaved food. Sand fly females were treated with an antibiotic cocktail to deplete gut bacteria and were experimentally infected by Leishmania. Compared to non-infected females, dorsal and defensin were upregulated at early and late infection stages, respectively. An earlier increase of defensin was observed in infected females when bacteria recolonized the gut after the removal of antibiotics. Interestingly, this defensin gene expression occurred specifically in midguts but not in other tissues of females and larvae. A gut-specific defensin gene upregulated by L. major infection, in combination with gut-bacteria, is a promising molecular target for parasite control strategies.

Resilient Built Environment: Critical Review of the Strategies Released by the Sustainability Rating Systems in Response to the COVID-19 Pandemic

Since the COVID-19 outbreak, buildings have been viewed as a facilitator of disease spread, where the three main transmission routes (contact, droplets, aerosols) are more likely to happen. However, with proper policies and measures, buildings can be better prepared for re-occupancy and beyond. This study reviews the strategies developed by several Sustainability Rating Systems (SRS, namely WELL, Fitwel and LEED) to respond to any infectious disease and ensure that building occupants protect and maintain their health. The best practices, that are similar between each SRS, highlight that the overall sustainability of the spaces increases if they are resilient. Results indicate that SRS promote a weak sustainability approach since they accept that economic development can reduce natural capitals. SRS are also characterized by an aggregated level of assessment of different criteria that does not allow to map different choices. However, the decomposition of the concept of sustainability in its three bottom lines (i.e., environmental, social and economic) shows that preventive strategies are likely to be systematically adopted as the state-of-the-art. Finally, even if the latest research points out the airborne transmission as the major infection route, the SRS lack analytical measures to address issues such as social distancing.

HIF-alpha Activation Impacts Macrophage Function During Murine Leishmania major Infection

Leishmanial skin lesions are characterized by inflammatory hypoxia alongside the activation of hypoxia inducible factors, HIF-1a and HIF-2a, and subsequent expression of the HIF-a target VEGF-A during Leishmania major infection. However, the factors responsible for HIF-a activation are not known. We hypothesize hypoxia and pro-inflammatory stimuli contribute to HIF-a activation during infection. RNASeq on leishmanial lesions found transcripts associated with HIF-1a signaling are induced. To determine whether hypoxia contributes to HIF-a activation, we followed the fate of myeloid cells infiltrating from the blood and into hypoxic lesions. Recruited myeloid cells experience hypoxia when they enter inflamed lesions, and the length of time in lesions increases their hypoxic signature. To determine whether pro-inflammatory stimuli in the inflamed tissue can also influence HIF-a activation, we subjected macrophages to various pro-inflammatory stimuli and measured VEGF-A. While parasites alone did not induce VEGF-A, and pro-inflammatory stimuli only modestly induce VEGF-A, HIF- stabilization increases VEGF-A during infection. HIF-a stabilization does not impact parasite entry, growth or killing. Alternatively, the absence of ARNT/HIF- signaling enhances parasite internalization. Altogether, these findings suggest HIF-a is active during infection, and while macrophage HIF-a activation promotes lymphatic remodeling through VEGF-A production, HIF-a activation does not impact parasite internalization or control.

In vivo reprogramming of murine host immune response genes following Leishmania major infection.

Leishmania parasites cause cutaneous leishmaniasis (CL), a pathologic disease characterized by disfiguring, ulcerative skin lesions. Both parasite and host gene expression following infection with various Leishmania species has been investigated in vitro, but global transcriptional analysis following L. major infection in vivo is lacking. Thus, we conducted a comprehensive transcriptomic profiling study combining bulk RNA sequencing (RNA-Seq) and single-cell RNA sequencing (scRNA-Seq) to identify global changes in gene expression in vivo following L. major infection. Bulk RNA-Seq analysis revealed that host immune response pathways like the antigen processing and presentation pathway were significantly enriched amongst differentially expressed genes (DEGs) upon infection, while ribosomal pathways were significantly downregulated in infected mice compared to naive controls. scRNA-Seq analyses revealed cellular heterogeneity including distinct resident and recruited cell types in the skin following murine L. major infection. Within the individual immune cell types, several DEGs indicative of many interferon induced GTPases and antigen presentation molecules were significantly enhanced in the infected ears including macrophages (Gbp2, H2-K1, H2-Aa, H2-Ab1), resident macrophages (H2-K1, H2-D1, Gbp4, Gbp8, Gbp2), and inflammatory monocytes (Gbp2, Gbp5, Gbp7, Gbp3). Ingenuity Pathway Analysis of scRNA-Seq data indicated the antigen presentation pathway was increased with infection, while EIF2 signaling is the top downregulated pathway followed by eIF4/p70S6k and mTOR signaling in multiple cell types including macrophages, BECs, and LECs. Altogether, this transcriptomic profile highlights known recruitment of myeloid cells to lesions and recognizes a previously undefined role for EIF2 signaling in murine L. major infection in vivo.

Distal Intra Articular Tibial Fracture Treated by Ilizarov with Ligamentotaxis

Background The thin soft tissue and muscles envelope that surrounds the distal tibia makes treatment of these fractures difficult. These fractures are often referred to as ―pilon‖ fractures or ―plafond‖ fractures‖. If the articular surface of the tibia is involved; in such cases an anatomic realignment of the involved articular fracture in conjunction with a stable fixation is crucial. Objectives The aim of this paper is to conduct a systematic review of literature about functional and radiological outcomes in patients with distal intra articular tibial fracture treated by external fixator with ligamentotaxis. Materials and Methods We performed this systematic review and meta-analysis in accordance to the recommendations of the Meta-analysis of Observational Studies in Epidemiology (MOOSE) statement. MOOSE is a reporting checklist for Authors, Editors, and Reviewers of Meta-analyses of interventional and observational studies. According to International committee of medical journal association (ICJME), reviewers must report their findings according to each of the items listed in those checklists Results Over all, five studies reported the time to union. The overall effect estimates showed that the time to union after Ilizarov external fixator was 12.83 weeks. Three studies reported the rate of union. The overall effect estimates showed that the rate of union after Ilizarov external fixator was 88.4%. Over all, eight studies reported the good-excellent AOFS score. The overall effect estimates showed that the rate of good-excellent AOFS score after Ilizarov external fixator was 69.4%. Nine studies reported the rate of malunion. The overall effect estimates showed that the rate of malunion after Ilizarov external fixator was 10.2%. Over all, seven studies reported the rate of delayed union. The overall effect estimates showed that the rate of delayed union after Ilizarov external fixator was 6.3%. All studies reported the rate of pin infection. The overall effect estimates showed that the rate of pin infection after Ilizarov external fixator was 33.7%. Ten studies reported the rate of major infection. The overall effect estimates showed that the rate of major infection after Ilizarov external fixator was 3.4. Conclusion External fixation and ligamentotaxis by either ilizarov or any external fixator is a good and easy method for fixation of distal intraarticulat tibial fracture with few serious complications. due to easy to apply it, less rate of infection, no risk of bleeding since no opening the fracture site, good aligment of the joint, no streaping of the periosteomy that lead to later on good and rapid healing of the fracture.

Effective Enteral Treatment of Antibiotic for Patient with Respiratory Failure and Septic Shock in the Intensive Care Unit

Background: Pneumonia is a lung infection involving pulmonary alveoli caused by microbes, including bacteria, viruses, and fungi. It is a major infection that causes hospitalization and death worldwide and exacts an enormous cost in economic and human terms. The study to assess clinical outcomes for a critically ill patient treated with an enteral antibiotic for bacterial pneumonia is still limited. Case: We reported a case of pneumonia from 68 years old patient that caused respiratory failure and septic shock in the intensive care unit treated by enteral antibiotic and had a good outcome. Conclusion: Pneumonia can cause respiratory failure and septic conditions. Optimum antibiotic management is one of the methods to solve this problem. The benefit of utilizing enteral antibiotics is substantial and probably appropriate in certain patients.