Could Intravenous Immunoglobulin Collected from Recovered Coronavirus Patients Protect against COVID-19 and Strengthen the Immune System of New Patients?

The emergence of the novel coronavirus in Wuhan, China, which causes severe respiratory tract infections in humans (COVID-19), has become a global health concern. Most coronaviruses infect animals but can evolve into strains that cross the species barrier and infect humans. At the present, there is no single specific vaccine or efficient antiviral therapy against COVID-19. Recently, we showed that intravenous immunoglobulin (IVIg) treatment reduces inflammation of intestinal epithelial cells and eliminates overgrowth of the opportunistic human fungal pathogen Candida albicans in the murine gut. Immunotherapy with IVIg could be employed to neutralize COVID-19. However, the efficacy of IVIg would be better if the immune IgG antibodies were collected from patients who have recovered from COVID-19 in the same city, or the surrounding area, in order to increase the chance of neutralizing the virus. These immune IgG antibodies will be specific against COVID-19 by boosting the immune response in newly infected patients. Different procedures may be used to remove or inactivate any possible pathogens from the plasma of recovered coronavirus patient derived immune IgG, including solvent/detergent, 60 °C heat-treatment, and nanofiltration. Overall, immunotherapy with immune IgG antibodies combined with antiviral drugs may be an alternative treatment against COVID-19 until stronger options such as vaccines are available.

Intravenous Immunoglobulin Therapy Eliminates Candida albicans and Maintains Intestinal Homeostasis in a Murine Model of Dextran Sulfate Sodium-Induced Colitis.

Intravenous immunoglobulin (IVIg) therapy has diverse anti-inflammatory and immunomodulatory effects and has been employed successfully in autoimmune and inflammatory diseases. The role of IVIg therapy in the modulation of intestinal inflammation and fungal elimination has not been yet investigated. We studied IVIg therapy in a murine model of dextran sulfate sodium (DSS)-induced colitis. Mice received a single oral inoculum of Candida albicans and were exposed to DSS treatment for 2 weeks to induce colitis. All mice received daily IVIg therapy starting on day 1 for 7 days. IVIg therapy not only prevented a loss of body weight caused by the development of colitis but also reduced the severity of intestinal inflammation, as determined by clinical and histological scores. IVIg treatment significantly reduced the Escherichia coli, Enterococcus faecalis, and C. albicans populations in mice. The beneficial effects of IVIg were associated with the suppression of inflammatory cytokine interleukin (IL)-6 and enhancement of IL-10 in the gut. IVIg therapy also led to an increased expression of peroxisome proliferator-activated receptor gamma (PPARγ), while toll-like receptor 4 (TLR-4) expression was reduced. IVIg treatment reduces intestinal inflammation in mice and eliminates C. albicans overgrowth from the gut in association with down-regulation of pro-inflammatory mediators combined with up-regulation of anti-inflammatory cytokines.

A Small Aromatic Compound Has Antifungal Properties and Potential Anti-Inflammatory Effects against Intestinal Inflammation.

Resistance of the opportunistic pathogen Candida albicans to antifungal drugs has increased significantly in recent years. After screening 55 potential antifungal compounds from a chemical library, 2,3-dihydroxy-4-methoxybenzaldehyde (DHMB) was identified as having potential antifungal activity. The properties of DHMB were then assessed in vitro and in vivo against C. albicans overgrowth and intestinal inflammation. Substitution on the aromatic ring of DHMB led to a strong decrease in its biological activity against C. albicans. The MIC of DHMB was highly effective at eliminating C. albicans when compared to that of caspofungin or fluconazole. Additionally, DHMB was also effective against clinically isolated fluconazole- or caspofungin-resistant C. albicans strains. DHMB was administered to animals at high doses. This compound was not cytotoxic and was well-tolerated. In experimental dextran sodium sulphate (DSS)-induced colitis in mice, DHMB reduced the clinical and histological score of inflammation and promoted the elimination of C. albicans from the gut. This finding was supported by a decrease in aerobic bacteria while anaerobic bacteria populations were re-established in mice treated with DHMB. DHMB is a small organic molecule with antifungal properties and anti-inflammatory activity by exerting protective effects on intestinal epithelial cells.

Distinct Effects of Integrins αXß2 and αMß2 on Leukocyte Subpopulations during Inflammation and Antimicrobial Responses.

Integrins αMß2 and αXß2 are homologous adhesive receptors that are expressed on many of the same leukocyte populations and bind many of the same ligands. Although αMß2 was extensively characterized and implicated in leukocyte inflammatory and immune functions, the roles of αXß2 remain largely obscure. Here, we tested the ability of mice deficient in integrin αMß2 or αXß2 to deal with opportunistic infections and the capacity of cells derived from these animals to execute inflammatory functions. The absence of αMß2 affected the recruitment of polymorphonuclear neutrophils (PMN) to bacterial and fungal pathogens as well as to model inflammatory stimuli, and αMß2-deficient PMN displayed defective inflammatory functions. In contrast, deficiency of αXß2 abrogated intraperitoneal recruitment and adhesive functions of monocytes and macrophages (Mϕ) and the ability of these cells to kill/phagocytose Candida albicans or Escherichia coli cells both ex vivo and in vivo During systemic candidiasis, the absence of αXß2 resulted in the loss of antifungal activity by tissue Mϕ and inhibited the production of tumor necrosis factor alpha (TNF-α)/interleukin-6 (IL-6) in infected kidneys. Deficiency of αMß2 suppressed Mϕ egress from the peritoneal cavity, decreased the production of anti-inflammatory IL-10, and stimulated the secretion of IL-6. The absence of αXß2, but not of αMß2, increased survival against a septic challenge with lipopolysaccharide (LPS) by 2-fold. Together, these results suggest that αMß2 plays a primary role in PMN inflammatory functions and regulates the anti-inflammatory functions of Mϕ, whereas αXß2 is central in the regulation of inflammatory functions of recruited and tissue-resident Mϕ.

Short fungal fractions of ß-1,3 glucans affect platelet activation.

Platelets are capable of binding, aggregating, and internalizing microorganisms, which enhances the elimination of pathogens from the blood. The yeast Candida albicans is a pathobiont causing life-threatening invasive infections. Its cell wall contains ß-1,3 glucans that are known to trigger a wide range of host cell activities and to circulate during infection. We studied the effect of ß-1,3 glucan fractions (BGFs) consisting of diglucosides (Glc2), tetraglucosides (Glc4), and pentaglucosides (Glc5) on human platelets, their mechanisms of action, and their possible impact on host defenses. The effect of BGFs on the coagulation process was determined by measuring thrombin generation. Platelets pretreated with BGFs were analyzed in terms of activation, receptor expression, aggregation, and adhesion to neutrophils and to C. albicans The results show that BGFs affected the endogenous thrombin potential in a concentration-dependent manner. For platelet activation, BGFs at a low concentration (2 µmol/l) reduced ATP release and prevented the phosphorylation of protein kinase C. BGFs diminished the expression of P-selectin and the activation of αIIbß3 BGFs decreased platelet aggregation and the interaction between thrombin-stimulated platelets and neutrophils, fibrinogen, and C. albicans GLc5 decreased ATP release and TGF-ß1 production in response to TLR4 upregulation in thrombin-stimulated platelets, but TLR4 blockage abolished the effect of BGFs on platelets. This study provides evidence that fungal pentaglucosides modulate platelet activity mediated via TLR4 stimulation and reduce platelet-neutrophil interaction.

Candida albicans airway exposure primes the lung innate immune response against Pseudomonas aeruginosa infection through innate lymphoid cell recruitment and interleukin-22-associated mucosal response.

Pseudomonas aeruginosa and Candida albicans are two pathogens frequently encountered in the intensive care unit microbial community. We have demonstrated that C. albicans airway exposure protected against P. aeruginosa-induced lung injury. The goal of the present study was to characterize the cellular and molecular mechanisms associated with C. albicans-induced protection. Airway exposure by C. albicans led to the recruitment and activation of natural killer cells, innate lymphoid cells (ILCs), macrophages, and dendritic cells. This recruitment was associated with the secretion of interleukin-22 (IL-22), whose neutralization abolished C. albicans-induced protection. We identified, by flow cytometry, ILCs as the only cellular source of IL-22. Depletion of ILCs by anti-CD90.2 antibodies was associated with a decreased IL-22 secretion and impaired survival after P. aeruginosa challenge. Our results demonstrate that the production of IL-22, mainly by ILCs, is a major and inducible step in protection against P. aeruginosa-induced lung injury. This cytokine may represent a clinical target in Pseudomonas aeruginosa-induced lung injury.

Integrin αXß2 is a leukocyte receptor for Candida albicans and is essential for protection against fungal infections.

The opportunistic fungus Candida albicans is one of the leading causes of infections in immunocompromised patients, and innate immunity provides a principal mechanism for protection from the pathogen. In the present work, the role of integrin α(X)ß2 in the pathogenesis of fungal infection was assessed. Both purified α(X)ß2 and α(X)ß2-expressing human epithelial kidney 293 cells recognized and bound to the fungal hyphae of SC5314 strain of C. albicans but not to the yeast form or to hyphae of a strain deficient in the fungal mannoprotein, Pra1. The binding of the integrin to the fungus was inhibited by ß-glucans but not by mannans, implicating a lectin-like activity in recognition but distinct in specificity from that of α(M)ß2. Mice deficient in α(X)ß2 were more prone to systemic infection with the LD50 fungal inoculum decreasing 3-fold in α(X)ß2-deficient mice compared with wild-type mice. After challenging i.v. with 1.5 × 104 cell/g, 60% of control C57BL/6 mice died within 14 d compared with 100% mortality of α(X)ß2-deficient mice within 9 d. Organs taken from α(X)ß2-deficient mice 16 h postinfection revealed a 10-fold increase in fungal invasion into the brain and a 2-fold increase into the liver. These data indicate that α(X)ß2 is important for protection against systemic C. albicans infections and macrophage subsets in the liver, Kupffer cells, and in the brain, microglial cells use α(X)ß2 to control fungal invasion.

Genetic diversity among Candida albicans isolates associated with vertical transmission in preterm triplets.

We report a case of congenital candidiasis in triplets, in the context of premature labor at 25 weeks gestation, without symptomatic vaginitis or chorioamnionitis. All three infants died as a result of prematurity, aggravated by systemic candidiasis. Multi-locus sequence typing confirmed vertical transmission of Candida albicans from the mother to the triplets and revealed a slight diversity among the strains isolated from the neonates.

How Do Polyphenol-Rich Foods Prevent Oxidative Stress and Maintain Gut Health?

Inflammatory bowel disease (IBD), which includes Crohn's disease and ulcerative colitis, involves chronic inflammatory disorders of the digestive tract. Oxidative stress, associated with increased reactive oxygen species generation, is a major risk factor for IBD pathogenesis. Industrialized lifestyles expose us to a variety of factors that contribute to deteriorating gut health, especially for IBD patients. Many alternative therapeutic strategies have been developed against oxidative stress along with conventional therapy to alleviate IBD pathogenesis. Polyphenol-rich foods have attracted growing interest from scientists due to their antioxidant properties. Polyphenols are natural compounds found in plants, fruits, vegetables, and nuts that exhibit antioxidant properties and protect the body from oxidative damage. This review presents an overview of polyphenol benefits and describes the different types of polyphenols. It also discusses polyphenols' role in inhibiting oxidative stress and fungal growth prevention. Overall, this review highlights how a healthy and balanced diet and avoiding the industrialized lifestyles of our modern society can minimize oxidative stress damage and protect against pathogen infections. It also highlights how polyphenol-rich foods play an important role in protecting against oxidative stress and fungal growth.

Murine model of dextran sulfate sodium-induced colitis reveals Candida glabrata virulence and contribution of ß-mannosyltransferases.

Candida glabrata, like Candida albicans, is an opportunistic yeast pathogen that has adapted to colonize all segments of the human gastrointestinal tract and vagina. The C. albicans cell wall expresses ß-1,2-linked mannosides (ß-Mans), promoting its adherence to host cells and tissues. Because ß-Mans are also present in C. glabrata, their role in C. glabrata colonization and virulence was investigated in a murine model of dextran sulfate sodium (DSS)-induced colitis. Five clustered genes of C. glabrata encoding ß-mannosyltransferases, BMT2-BMT6, were deleted simultaneously. ß-Man expression was studied by Western blotting, flow cytometry, and NMR analysis. Mortality, clinical, histologic, and colonization scores were determined in mice receiving DSS and different C. glabrata strains. The results show that C. glabrata bmt2-6 strains had a significant reduction in ß-1,2-Man expression and a disappearance of ß-1,2-mannobiose in the acid-stable domain. A single gavage of C. glabrata wild-type strain in mice with DSS-induced colitis caused a loss of body weight, colonic inflammation, and mortality. Mice receiving C. glabrata bmt2-6 mutant strains had normal body weight and reduced colonic inflammation. Lower numbers of colonies of C. glabrata bmt2-6 were recovered from stools and different parts of the gastrointestinal tract. Histopathologic examination revealed that the wild-type strain had a greater ability to colonize tissue and cause tissue damage. These results showed that C. glabrata has a high pathogenic potential in DSS-induced colitis, where ß-Mans contribute to colonization and virulence.

Healthy Diet and Lifestyle Improve the Gut Microbiota and Help Combat Fungal Infection.

Western diets are rapidly spreading due to globalization, causing an increase in obesity and diseases of civilization. These Western diets are associated with changes in the gut microbiota related to intestinal inflammation. This review discusses the adverse effects of Western diets, which are high in fat and sugar and low in vegetable fiber, on the gut microbiota. This leads to gut dysbiosis and overgrowth of Candida albicans, which is a major cause of fungal infection worldwide. In addition to an unhealthy Western diet, other factors related to disease development and gut dysbiosis include smoking, excessive alcohol consumption, lack of physical activity, prolonged use of antibiotics, and chronic psychological stress. This review suggests that a diversified diet containing vegetable fiber, omega-3 polyunsaturated fatty acids, vitamins D and E, as well as micronutrients associated with probiotic or prebiotic supplements can improve the biodiversity of the microbiota, lead to short-chain fatty acid production, and reduce the abundance of fungal species in the gut. The review also discusses a variety of foods and plants that are effective against fungal overgrowth and gut dysbiosis in traditional medicine. Overall, healthy diets and lifestyle factors contribute to human well-being and increase the biodiversity of the gut microbiota, which positively modulates the brain and central nervous system.

Editorial of Special Issue "Human Pathogenic Fungi: Host-Pathogen Interactions and Virulence".

Most individuals harbour several species of yeast of the genus Candida, which are considered true symbionts of the human gut microbiota [...].

Anti-Malassezia Drug Candidates Based on Virulence Factors of Malassezia-Associated Diseases.

Malassezia is a lipophilic unicellular fungus that is able, under specific conditions, to cause severe cutaneous and systemic diseases in predisposed subjects. This review is divided into two complementary parts. The first one discusses how virulence factors contribute to Malassezia pathogenesis that triggers skin diseases. These virulence factors include Malassezia cell wall resistance, lipases, phospholipases, acid sphingomyelinases, melanin, reactive oxygen species (ROS), indoles, hyphae formation, hydrophobicity, and biofilm formation. The second section describes active compounds directed specifically against identified virulence factors. Among the strategies for controlling Malassezia spread, this review discusses the development of aryl hydrocarbon receptor (AhR) antagonists, inhibition of secreted lipase, and fighting biofilms. Overall, this review offers an updated compilation of Malassezia species, including their virulence factors, potential therapeutic targets, and strategies for controlling their spread. It also provides an update on the most active compounds used to control Malassezia species.

Antifungal Properties of Hydrazine-Based Compounds against Candida albicans.

Candida albicans, an opportunistic yeast, is the most common cause of fungal infection. In the past decade, there has been an increase in C. albicans resistance to existing antifungal drugs, which has necessitated the development of new antifungal agents. In the present study, screening 60 compounds from the JUNIA chemical library enabled us to explore an additional 11 hybrid compounds that contain pyrrolidinone rings and hydrazine moieties for their potential antifungal activities. This chemical series was identified with fair to excellent antifungal activities. Among this series, three molecules (Hyd.H, Hyd.OCH3, and Hyd.Cl) significantly reduced C. albicans viability, with rapid fungicidal activity. In addition, these three compounds exhibited significant antifungal activity against clinically isolated fluconazole- or caspofungin-resistant C. albicans strains. Hyd.H, Hyd.OCH3, and Hyd.Cl did not show any cytotoxicity against human cancer cell lines up to a concentration of 50 µg/mL and decreased Candida biofilm formation, with a significant reduction of 60% biofilm formation with Hyd.OCH3. In an infection model of Caenorhabditis elegans with C. albicans, hydrazine-based compounds significantly reduced nematode mortality. Overall, fungicidal activity was observed for Hyd.H, Hyd.OCH3, and Hyd.Cl against C. albicans, and these compounds protected C. elegans from C. albicans infection.

Natural Compounds with Antifungal Properties against Candida albicans and Identification of Hinokitiol as a Promising Antifungal Drug.

Candida albicans is an opportunistic yeast that causes most fungal infections. C. albicans has become increasingly resistant to antifungal drugs over the past decade. Our study focused on the identification of pure natural compounds for the development of antifungal medicines. A total of 15 natural compounds from different chemical families (cinnamic derivatives, aromatic phenols, mono- and sesquiterpenols, and unclassified compounds) were screened in this study. Among these groups, hinokitiol (Hi), a natural monoterpenoid extracted from the wood of the cypress family, showed excellent anti-C. albicans activity, with a MIC value of 8.21 µg/mL. Hi was selected from this panel for further investigation to assess its antifungal and anti-inflammatory properties. Hi exhibited significant antifungal activity against clinically isolated fluconazole- or caspofungin-resistant C. albicans strains. It also reduced biofilm formation and hyphal growth. Treatment with Hi protected Caenorhabditis elegans against infection with C. albicans and enhanced the expression of antimicrobial genes in worms infected with C. albicans. Aside from its antifungal activities against C. albicans, Hi challenge attenuated the LPS-induced expression of pro-inflammatory cytokines (IL-6, IL-1ß, and CCL-2) in macrophages. Overall, Hi is a natural compound with antifungal and anti-inflammatory properties, making Hi a promising platform with which to fight against fungal infections.

Mannose-binding lectin levels and variation during invasive candidiasis.

The high morbi-mortality associated with invasive candidiasis (IC) is a persistent problem in hospitals. Mannose-binding lectin (MBL) plays a role in innate immunity through its interaction with mannosylated molecules of Candida albicans. A correlation between MBL deficiency and vulvovaginal candidiasis or peritonitis has been reported. We investigated circulating MBL levels and their evolution during the course of IC. Sixty-eight patients with proven IC, 82 hospitalized patients (HP) without evidence of infection, and 70 healthy subjects (HS) were studied in order to examine the relationship between serum MBL and IC. Serum MBL levels were measured by enzyme-linked immunosorbent assay (ELISA). MBL levels were significantly higher in IC patients than in HP and HS (p < 0.0001, p < 0.0055, respectively). A change in MBL concentrations was observed during the course of IC, with a dramatic decrease during the 2 days before positive blood culture sampling. This decrease was concomitant with the presence of high levels of circulating mannan (Mn). Like MBL levels, anti-mannan antibodies (AMn) increased after the mannanemia/blood culture period. These findings suggest a possible role of MBL during the early stage of IC. The mechanisms that regulate these observations in terms of effect and consequences on innate and adaptive immunity and the prognosis of IC require further investigation.

How Gut Bacterial Dysbiosis Can Promote Candida albicans Overgrowth during Colonic Inflammation.

Candida albicans is a commensal opportunistic yeast, which is capable of colonising many segments of the human digestive tract. Excessive C. albicans overgrowth in the gut is associated with multiple risk factors such as immunosuppression, antibiotic treatment associated with changes to the gut microbiota and digestive mucosa that support C. albicans translocation across the digestive intestinal barrier and haematogenous dissemination, leading to invasive fungal infections. The C. albicans cell wall contains mannoproteins, ß-glucans, and chitin, which are known to trigger a wide range of host cell activities and to circulate in the blood during fungal infection. This review describes the role of C. albicans in colonic inflammation and how various receptors are involved in the immune defence against C. albicans with a special focus on the role of mannose-binding lectin (MBL) and TLRs in intestinal homeostasis and C. albicans sensing. This review highlights gut microbiota dysbiosis during colonic inflammation in a dextran sulphate sodium (DSS)-induced colitis murine model and the effect of fungal glycan fractions, in particular ß-glucans and chitin, on the modification of the gut microbiota, as well as how these glycans modulate the immuno-inflammatory response of the host.

Oleic Acid and Palmitic Acid from Bacteroides thetaiotaomicron and Lactobacillus johnsonii Exhibit Anti-Inflammatory and Antifungal Properties.

A decrease in populations of Bacteroides thetaiotaomicron and Lactobacillus johnsonii is observed during the development of colitis and fungal overgrowth, while restoration of these populations reduces inflammatory parameters and fungal overgrowth in mice. This study investigated the effect of two fatty acids from B. thetaiotaomicron and L. johnsonii on macrophages and Caco-2 cells, as well as their impact on the inflammatory immune response and on Candida glabrata overgrowth in a murine model of dextran sulfate sodium (DSS)-induced colitis. Oleic acid (OA) and palmitic acid (PA) from L. johnsonii and B. thetaiotaomicron were detected during their interaction with epithelial cells from colon samples. OA alone or OA combined with PA (FAs) reduced the expression of proinflammatory mediators in intestinal epithelial Caco-2 cells challenged with DSS. OA alone or FAs increased FFAR1, FFAR2, AMPK, and IL-10 expression in macrophages. Additionally, OA alone or FAs decreased COX-2, TNFα, IL-6, and IL-12 expression in LPS-stimulated macrophages. In the DSS murine model, oral administration of FAs reduced inflammatory parameters, decreased Escherichia coli and Enterococcus faecalis populations, and eliminated C. glabrata from the gut. Overall, these findings provide evidence that OA combined with PA exhibits anti-inflammatory and antifungal properties.

Two New Compounds Containing Pyridinone or Triazine Heterocycles Have Antifungal Properties against Candida albicans.

Candidiasis, caused by the opportunistic yeast Candida albicans, is the most common fungal infection today. Resistance of C. albicans to current antifungal drugs has emerged over the past decade leading to the need for novel antifungal agents. Our aim was to select new antifungal compounds by library-screening methods and to assess their antifungal effects against C. albicans. After screening 90 potential antifungal compounds from JUNIA, a chemical library, two compounds, 1-(4-chlorophenyl)-4-((4-chlorophenyl)amino)-3,6-dimethylpyridin-2(1H)-one (PYR) and (Z)-N-(2-(4,6-dimethoxy-1,3,5-triazin-2-yl)vinyl)-4-methoxyaniline (TRI), were identified as having potential antifungal activity. Treatment with PYR and TRI resulted in a significant reduction of C. albicans bioluminescence as well as the number of fungal colonies, indicating rapid fungicidal activity. These two compounds were also effective against clinically isolated fluconazole- or caspofungin-resistant C. albicans strains. PYR and TRI had an inhibitory effect on Candida biofilm formation and reduced the thickness of the mannan cell wall. In a Caenorhabditis elegans infection model, PYR and TRI decreased the mortality of nematodes infected with C. albicans and enhanced the expression of antimicrobial genes that promote C. albicans elimination. Overall, PYR and TRI showed antifungal properties against C. albicans by exerting fungicidal activities and enhancing the antimicrobial gene expression of Caenorhabditis elegans.

Identification of fungal trehalose for the diagnosis of invasive candidiasis by mass spectrometry.

The rapidity of the diagnosis of invasive candidiasis (IC) is crucial to allow the early introduction of antifungal therapy that dramatically increases the survival rate of patients. Early diagnosis is unfortunately often delayed because Candida blood culture, the gold standard diagnostic test, is positive in only 50% of cases of IC and takes several days to obtain this result. Complementary non-culture-based methods relying on the detection of Candida cell wall polysaccharides in the serum, ß-glucans and mannans, by enzymatic and immunological reagents have been successfully developed to allow a more efficient patients care. We have previously demonstrated that detection of circulating glycans by mass spectrometry could provide a reliable and cost-effective early diagnosis method called MS-DS for Mass Spectrometry of Di-Saccharide. Here, by comparing patient's sera and Candida albicans strains deficient in carbohydrates synthesis, we demonstrate that trehalose derived from fungal metabolism can be specifically targeted by MS-DS to allow early diagnosis. In particular, the use of C. albicans strains deficient in the synthesis of trehalose synthesizing enzymes Tps1 and Tps2 show that MS-DS results were correlated to the metabolism of trehalose. Finally, we demonstrate that the performance of the IC diagnosis can be significantly improved by using high resolution mass spectrometry, which opens new perspectives in the management of the disease.