Candida species and Aspergillus fumigatus were once thought to be relatively benign organisms. However, it is now known that this is not the case - Candida species rank among the top four causes of nosocomial infectious diseases in humans and A. fumigatus is the most deadly mould, often having a 90% mortality rate in immunocompromised transplant recipients. Adaptation to stress, including oxidative stress, is a necessary requisite for survival of these organisms during infection. Here, we describe the latest information on the signalling pathways and target proteins that contribute to oxidant adaptation in C. albicans and A. fumigatus, which has been obtained primarily through the analysis of mutants or inference from genome annotation.

Signalling and oxidant adaptation in Candida albicans and Aspergillus fumigatus

Invasive fungal infections are a significant health problem in immunocompromised patients. The clinical manifestations vary and can range from colonization in allergic bronchopulmonary disease to active infection in local aetiologic agents. Many factors influence the virulence and pathogenic capacity of the microorganisms, such as enzymes including extracellular phospholipases, lipases and proteinases, dimorphic growth in some Candida species, melanin production, mannitol secretion, superoxide dismutase, rapid growth and affinity to the blood stream, heat tolerance and toxin production. Infection is confirmed when histopathologic examination with special stains demonstrates fungal tissue involvement or when the aetiologic agent is isolated from sterile clinical specimens by culture. Both acquired and congenital immunodeficiency may be associated with increased susceptibility to systemic infections. Fungal infection is difficult to treat because antifungal therapy for Candida infections is still controversial and based on clinical grounds, and for molds, the clinician must assume that the species isolated from the culture medium is the pathogen. Timely initiation of antifungal treatment is a critical component affecting the outcome. Disseminated infection requires the use of systemic agents with or without surgical debridement, and in some cases immunotherapy is also advisable. Preclinical and clinical studies have shown an association between drug dose and treatment outcome. Drug dose monitoring is necessary to ensure that therapeutic levels are achieved for optimal clinical efficacy. The objectives of this review are to discuss opportunistic fungal infections, diagnostic methods and the management of these infections.

Opportunistic invasive fungal infections: diagnosis & clinical management

Immunity to fungi.

Invasive aspergillosis is among the most common human fungal infections and occurs in patients with severe and complex defects in immune responses. NK cells have previously been found to be important in host defense against this infection, but the mechanism of this effect is not known. We hypothesized that NK cells mediate their protective effect in invasive aspergillosis by acting as the major source of IFN-γ during early infection. We found that, in the lungs of neutropenic mice with invasive aspergillosis, NK cells were the major population of cells capable of generating IFN-γ during early infection. Depletion of NK cells resulted in reduced lung IFN-γ levels and increased lung fungal load that was independent of T and B cell subsets. Depletion of NK cells and absence of IFN-γ resulted in a similar increase in susceptibility to the infection, but depletion of NK cells in IFN-γ-deficient hosts did not result in further increase in severity of the infection. NK cell-derived IFN-γ caused enhanced macrophage antimicrobial effects in vitro and also resulted in greater expression of IFN-inducible chemokines in the lungs. Finally, transfer of activated NK cells from wild-type, but not IFN-γ-deficient hosts, resulted in greater pathogen clearance from the lungs of both IFN-γ-deficient and wild-type recipients. Taken together, these data indicate that NK cells are the main source of early IFN-γ in the lungs in neutropenic invasive aspergillosis, and this is an important mechanism in the defense against this infection.

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Early NK Cell-Derived IFN-γ Is Essential to Host Defense in Neutropenic Invasive Aspergillosis

Despite the strong interest in the NK cell-mediated immunity toward malignant cells and viruses, there is a relative lack of data on the interplay between NK cells and filamentous fungi, especially Aspergillus fumigatus, which is the major cause of invasive aspergillosis. By studying the in vitro interaction between human NK cells and A. fumigatus, we found only germinated morphologies to be highly immunogenic, able to induce a Th1-like response, and capable of upregulating cytokines such as IFN-γ and TNF-α. Moreover, priming NK cells with human rIL-2 and stimulating NK cells by direct NK cell-pathogen contact were essential to induce damage against A. fumigatus. However, the most interesting finding was that NK cells did not mediate anti-Aspergillus cytotoxicity through degranulation of their cytotoxic proteins (perforin, granzymes, granulysine), but via an alternative mechanism involving soluble factor(s). To our knowledge, our study is the first to demonstrate that IFN-γ, released by NK cells, directly damages A. fumigatus, attributing new properties to both human NK cells and IFN-γ and suggesting them as possible therapeutic tools against IA.

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Human NK cells display important antifungal activity against Aspergillus fumigatus, which is directly mediated by IFN-γ release.

To understand virus and host interactions and host responses to rotavirus infection in children, we analysed by real-time polymerase chain reaction (PCR) the expression of mRNA for five Toll-like receptors (TLRs) (TLR2, TLR3, TLR4, TLR7 and TLR8) and four T helper (Th)1 and Th2 cytokines [interleukin (IL)-2, IL-12, interferon (IFN)-gamma and IL-4) in peripheral blood mononuclear cells (PBMC) of children with acute rotavirus diarrhoea. We observed significantly higher expression of genes encoding TLR2, TLR3, TLR4, TLR7 and TLR8 in PBMC of 41% (31/75) patients within 3 days of illness onset than those in healthy children. After 3 days of illness onset, only TLR3 and TLR8 mRNA expressions were still significantly (P<0.05) increased in 59% (44/75) children with diarrhoea. We also observed significantly (P<0.05) elevated expression of IL-12p40 and IFN-gamma in PBMC of patients during the entire period of illness and the first 3 days of illness, respectively. We further demonstrated a weak but significant association between elevated levels of gene expression of four TLRs (TLR2, TLR3, TLR4 and TLR8) and IFN-gamma. Our results suggest that multiple TLRs may modulate the immune response in the acute phase of rotavirus infection and play a role in the activation of IFN-gamma.

Expression of Toll-like receptors and their association with cytokine responses in peripheral blood mononuclear cells of children with acute rotavirus diarrhoea.

Cytokines are critical molecules necessary for normal lung pathogen host defences. Gamma interferon (IFN-gamma) and T1-phenotype immune responses are important components of host defence against Aspergillus. Therefore, we hypothesized that transient overexpression of IFN-gamma within the lung could augment host immunity against Aspergillus. Here it was showed that intranasal administration of 5 x 10(7) colony-forming units (CFU) of Aspergillus fumigatus (Af ) induced the expression of IFN-gamma. Mice were intranasally (i.n) administrated with 5 x 10(8) PFU of a recombinant adenovirus vector containing the murine IFN-gamma cDNA (AdmIFN-gamma), and challenged 24 h later with Af. We observed that i.n. administration of AdmIFN-gamma resulted in about a fourfold increase in levels of IFN-gamma and IL-12 within the lung, about a 75% reduction in lung fungal contents at day 2 and a more than threefold higher survival rate in the AdmIFN-gamma-treated group compared to the controls (P < 0.01). This protection effect was not found when AdmIFN-gamma was i.p. administrated. Alveolar macrophages and lung leucocytes isolated from i.n. AdmIFN-gamma-treated animals displayed enhanced killing of intracellular Aspergillus organisms ex vivo. These results demonstrate that transient overexpression of IFN-gamma could augment host defence against Aspergillus.

Transient overexpression of γ interferon promotes Aspergillus clearance in invasive pulmonary aspergillosis

Abstract Background Signal transducer and activator of transcription 6 (STAT6) is an intracelluar transcriotion factor and NLRP3 (Nod-like receptor containing a pyrin domain 3) is a component of NLRP3 inflammasome in pyroptotic cells. There was increased activation of STAT6 and expression of NLRP3 in mice with murine acute lung injury (ALI). However, it is unknown their roles in the development of murine ALI. We in this study, investigated the effects of STAT6 signaling on murine ALI and pyroptosis in STAT6 knock-out (KO) mice and macrophages. Results STAT6 was activated in the lung tissues of mice 2 days after intratracheal treatmemt with 5 mg/kg LPS. Lack of STAT6 expression in KO mice induced more severe lung inflammation, associated with elevated neutrophil influx and expression of TNF-alpha, IL-6 and IL-1beta in the inflamed lung tissues. In addition, the expression of NLRP3, ASC (apoptosis-associated speck-like protein containing a CARD), p-p38 MAPK (p38 mitogen-activated protein kinase) and ratio of LC3-II/I (microtubule-associated protein-1 light chain-3) was increased, accompanied with the increased polarization of Siglec-F(−) subtype macrophages in KO mice with ALI. Further studies in bone marrow-derived macrophages (BMDMs) revealed that lack of STAT6 increased the expression of NLRP3 and p-p38 MAPK, in association with elevated expression of TNF-alpha, IL-1beta and Calreticulin in LPS-treated KO BMDMs. Conclusions Lack of STAT6 exacerbated murine ALI through improving the expression of NLRP3 and activation of p38 MAPK in macrophages. STAT6 has an immune suppressive role in the development of ALI and would be a promising therapeutic target in the treatment of ALI and possibly among patients with acute respiratory distress syndrome (ARDS). 

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Lack of STAT6 enhances murine acute lung injury through NLRP3/p38 MAPK signaling pathway in macrophages

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INTRODUCTION
Research on the association between albumin (ALB) level and clinical outcomes of coronavirus disease 2019 (COVID-19) are limited. This study aimed to investigate the relationship between albumin level at the time of admission and adverse outcomes in patients with COVID-19.


METHODOLOGY
This was a retrospective cohort study with 199 COVID-19 patients from five designated hospitals in Fujian Province who were enrolled between 22 January and 27 February, 2020. Clinical characteristics and laboratory values at the time of admission were collected. Adverse outcomes were defined as meeting at least one of the following criteria: development of acute respiratory distress syndrome (ARDS), respiratory failure, shock, multiple organ failure (MOF), intensive care unit (ICU) admission and in-hospital mortality event. The univariate and multivariate linear regression models and generalized additive models (GAM) were used to analyze the relationship between ALB and adverse outcomes.


RESULTS
A non-linear relationship with an inflection point of 32.6g/L was detected between ALB and adverse outcomes after adjusting for potential confounders. The odds ratio and the confidence intervals on the left and right sides of the inflection point were 0.204 (0.061-0.681) and 0.908 (0.686-1.203), respectively. This suggested that ALB was negatively correlated with adverse outcomes when ALB was less than 32.6 g/L, and for every 1 unit increase in ALB, the risk of adverse outcomes was reduced by 79.6%.


CONCLUSIONS
The relationship between ALB and adverse outcomes of COVID-19 is non-linear. ALB level is an independent predictive factor for adverse outcomes in COVID-19 patients.

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C. Shao

Papers

Expression of Toll-like receptors and their association with cytokine responses in peripheral blood mononuclear cells of children with acute rotavirus diarrhoea.

Transient overexpression of γ interferon promotes Aspergillus clearance in invasive pulmonary aspergillosis

Lack of STAT6 enhances murine acute lung injury through NLRP3/p38 MAPK signaling pathway in macrophages

Lack of STAT6 enhances murine acute lung injury through NLRP3/p38 MAPK signaling pathway in macrophages

Albumin level as an independent predictive factor for adverse outcomes in COVID-19 patients: a retrospective cohort study.