COVID-19 Associated Rhino-Orbital-Cerebral Mucormycosis - An Institutional Series

Invasive fungal infection or mucormycosis is almost always confined to the patients with altered host defenses such as in transplant recipients, diabetics or patients with malignancies. Hypergycemia or uncontrolled diabetes, particularly diabetes acidosis is considered as the strongest and very well known risk factor for mucormycosis. It has spread like fire amongst the active COVID-19 and post COVID-19 diabetic patients. Many studies across the world have established the definitive severity of SARS-CoV-2 infection amongst diabetic patients.

Untargeted Metabolomic Investigation of Wheat Infected with Stinking Smut Tilletia caries

Tilletia caries infection of wheat (Triticum aestivum) has become an increasing problem in organic wheat agriculture throughout the world. Little is known about how this pathogen alters host metabolism to ensure a successful infection. We investigated how T. caries allocates resources from wheat for its growth over the life cycle of the pathogen. An untargeted metabolomics approach that combined gas chromatography time-of-flight mass spectrometry and ultraperformance liquid chromatography tandem mass spectrometry platforms was used to determine which primary or specialized metabolite pathways are targeted and altered during T. caries infection. We found that T. caries does not dramatically alter the global metabolome of wheat but instead alters key metabolites for its own nutrient uptake and to antagonize host defenses by reducing wheat’s sweet immunity response and other related pathways. Our results highlight metabolic characteristics needed for selecting wheat varieties that are resistant to T. caries infection for organic agriculture. In addition, several wheat metabolites were identified that could be used in developing a diagnostic tool for early detection of T. caries infection.

Inflammasome-mediated GSDMD activation facilitates escape of Candida albicans from macrophages

Candida albicans is the most common cause of fungal sepsis. Inhibition of inflammasome activity confers resistance to polymicrobial and LPS-induced sepsis; however, inflammasome signaling appears to protect against C. albicans infection, so inflammasome inhibitors are not clinically useful for candidiasis. Here we show disruption of GSDMD, a known inflammasome target and key pyroptotic cell death mediator, paradoxically alleviates candidiasis, improving outcomes and survival of Candida-infected mice. Mechanistically, C. albicans hijacked the canonical inflammasome-GSDMD axis-mediated pyroptosis to promote their escape from macrophages, deploying hyphae and candidalysin, a pore-forming toxin expressed by hyphae. GSDMD inhibition alleviated candidiasis by preventing C. albicans escape from macrophages while maintaining inflammasome-dependent but GSDMD-independent IL-1β production for anti-fungal host defenses. This study demonstrates key functions for GSDMD in Candida’s escape from host immunity in vitro and in vivo and suggests that GSDMD may be a potential therapeutic target in C. albicans-induced sepsis.

Innate Bacteriostatic Mechanisms Defend the Urinary Tract

Urinary tract infection (UTI) is the most common type of urogenital disease. UTI affects the urethra, bladder, ureter, and kidney. A total of 13.3% of women, 2.3% of men, and 3.4% of children in the United States will require treatment for UTI. Traditionally, bladder (cystitis) and kidney (pyelonephritis) infections are considered independently. However, both infections induce host defenses that are either shared or coordinated across the urinary tract. Here, we review the chemical and biophysical mechanisms of bacteriostasis, which limit the duration and severity of the illness. Urinary bacteria attempt to overcome each of these defenses, complicating description of the natural history of UTI. Expected final online publication date for the Annual Review of Physiology, Volume 84 is February 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Risk of an Adverse Event in Individuals Who Aspirate: A Review of Current Literature on Host Defenses and Individual Differences

Purpose The presence of oropharyngeal dysphagia increases the likelihood of prandial aspiration, and aspiration increases the likelihood of a dysphagia-related pulmonary sequelae such as aspiration pneumonia, acute respiratory distress syndrome, pulmonary fibrosis, and even death. Although these outcomes are unfortunate, it is important to point out that these consequences are not solely determined by the presence of aspiration. The purpose of this tutorial is to provide current information on pulmonary defenses and the variables that increase risk of an adverse outcome in individuals who aspirate. Method This tutorial reviews the basics of lung defenses and summarizes the literature to make the case that the host is a central theme in dysphagia management. Case studies are employed to highlight the key variables. Results Based on a literature review, a series of questions are proposed for consideration in dysphagia management. These questions, which take the focus away from the presence of aspiration and toward the associated risks within an individual, are then applied to two case studies. Conclusions A guiding framework is proposed to encourage clinicians to assess more than the presence of aspiration and consider the individual's ability to cope with the aspirated material. In the presence of aspiration, clinicians are urged to focus on the risk factors that can lead to a negative consequence, identify which factors are modifiable, and determine when a level of risk is acceptable.

Inflammatory phenotype modulation in the respiratory tract and systemic circulation of e-cigarette users: a pilot study

Over 40 million people use e-cigarettes worldwide, but the impact of chronic e-cigarette use on health has not been adequately defined. In particular, effects of e-cigarette aerosol inhalation on inflammation and host defenses across the body are not fully understood. We conducted a longitudinal cohort pilot study to explore changes in the inflammatory state and monocyte function of e-cigarette users (n=20) versus healthy controls (n=13), and to evaluate effects of e-cigarette use reduction on the same. Saliva, sputum, and blood were obtained from e-cigarette users at baseline and after a 2-week intervention of decreased e-cigarette use. Overall, across 38 proteins quantified by multiplex, airway samples from e-cigarette users tended to have decreased levels of immunomodulatory proteins relative to healthy controls, while levels of cytokines, chemokines and growth factors in the circulation tended to be elevated. Specifically, e-cigarette users had lower levels of IL-1 receptor antagonist (IL-1Ra) in saliva (p<0.0001), with higher IL-1Ra and GRO levels in sputum (p<0.01 and p<0.05, respectively), and higher levels of both TNFβ (p<0.0001) and VEGF (p<0.0001) in plasma. Circulating monocytes from e-cigarette users had alterations in their inflammatory phenotype in response to reduced e-cigarette use, with blunted IL-8 and IL-6 release upon challenge with bacterial lipopolysaccharide (p<0.001 and p<0.05, respectively), suggesting a decreased ability to appropriately respond to bacterial infection. Based on these findings, chronic inhalation of e-cigarette aerosols alters the inflammatory state of the airways and systemic circulation, raising concern for the development of both inflammatory and infectious diseases in chronic users of e-cigarettes.

Surgical Site Infection in Cancer Patients

Surgical site infection (SSI) incidence is affected by 3 types of interacting factors: the infecting organisms (eg, number, type, virulence), the local wound environment (eg, foreign matter, aseptic technique, wound dressings), and systemic host defenses (eg, smoking, obesity, diabetes). Cancer or related chemotherapy and other aspects of cancer care may affect host defenses, as evidenced by increased SSI risk following “clean” surgery to remove breast cancer tissue compared with similar “clean” surgeries in patients who do not have cancer. If patient risk factors for development of an SSI are strictly controlled in individuals undergoing breast cancer surgery, the likelihood of the development of an SSI drops sharply, creating the illusion that preoperative antibiotics are not needed. This Evidence Corner, which includes 2 studies, clarifies evidence supporting the use of recognized preoperative antibiotic administration to support host defenses in patients undergoing breast cancer surgery. In the first study, the controversy about wound dressings following cancer surgery is also explored. Some surgeons question whether routine use of gauze dressings promotes the ideal local wound environment after surgical excision of cancerous tissue. Disintegrating gauze strands can act as foreign bodies in wounds, and gauze dressings have been reported to increase SSI incidence in clean surgical wounds. The second study compared healing and SSI incidence of Mohs surgical excisions dressed with either an antibiotic-free, film-forming silicone wound dressing or a triple antibiotic primary dressing following Mohs micrographic or non-Mohs dermatologic surgery. The surprising results reinforce the importance of the local wound environment as a key factor in minimizing SSI in oncologic surgery.

The NF-κB Pathway: Modulation by Entamoeba histolytica and Other Protozoan Parasites

Protozoan parasites have led to worldwide devastation because of their ability to cause infectious diseases. They have evolved as successful pathogens in part because of their remarkable and sophisticated ways to evade innate host defenses. This holds true for both intracellular and extracellular parasites that deploy multiple strategies to circumvent innate host defenses for their survival. The different strategies protozoan parasites use include hijacking the host cellular signaling pathways and transcription factors. In particular, the nuclear factor-κB (NF-κB) pathway seems to be an attractive target for different pathogens owing to their central role in regulating prompt innate immune responses in host defense. NF-κB is a ubiquitous transcription factor that plays an indispensable role not only in regulating immediate immune responses against invading pathogens but is also a critical regulator of cell proliferation and survival. The major immunomodulatory components include parasite surface and secreted proteins/enzymes and stimulation of host cells intracellular pathways and inflammatory caspases that directly or indirectly interfere with the NF-κB pathway to thwart immune responses that are directed for containment and/or elimination of the pathogen. To showcase how protozoan parasites exploits the NF-κB signaling pathway, this review highlights recent advances from Entamoeba histolytica and other protozoan parasites in contact with host cells that induce outside-in and inside-out signaling to modulate NF-κB in disease pathogenesis and survival in the host.

Mycobacterium tuberculosis Rv0927c Inhibits NF-κB Pathway by Downregulating the Phosphorylation Level of IκBα and Enhances Mycobacterial Survival

Through long-term coevolution with its host, Mycobacterium tuberculosis (M. tuberculosis) uses multiple strategies to escape host defenses. The M. tuberculosis Rv0927c protein is predicted to be a short-chain dehydrogenase/reductase related to bacterial metabolism. However, the role of Rv0927c during M. tuberculosis infection remains unclear. Here, we observed that Rv0927c inhibited the expression of IL-6, TNF-α, and IL-1β, an effect dependent on NF-κB and p38 pathways. Western blot analysis of macrophages infected with recombinant Mycobacterium smegmatis strains showed that Rv0927c attenuated NF-κB activation by downregulating the phosphorylation of IκBα. Additionally, Rv0927c enhanced intracellular survival of M. smegmatis and pathological effects in mice. In conclusion, our findings demonstrate that Rv0927c functions as a regulator of inflammatory genes and enhances the survival of M. smegmatis.

Gut microbial signature and gut-lung axis: A possible role in the therapy of COVID-19

The impact of gut as the origin of different disorders has led to the "gut-origin concept" of diseases. The gut microbiome regulates host defenses against viral infections, thus dysbiosis can play a major role in triggering the cascade of inflammation and causing immune imbalances in COVID-19 patients. It appears that gut microbial signature in COVID-19 patients can be used as a potential diagnostic, therapeutic, and even a prognostic marker. Personalized nutrition therapy can be used by profiling the gut microbiota of individual patients and specialized probiotics/synbiotics to modify gut dysbiosis. Hence, improving overall immune responses can be recommended in these patients.