Immunocompromised Humans Research Articles

Continuing Shifts in Epidemiology and Antifungal Susceptibility Highlight the Need for Improved Disease Management of Invasive Candidiasis.

Invasive candidiasis (IC) is a systemic life-threatening infection of immunocompromised humans, but remains a relatively neglected disease among public health authorities. Ongoing assessments of disease epidemiology are needed to identify and map trends of importance that may necessitate improvements in disease management and patient care. Well-established incidence increases, largely due to expanding populations of patients with pre-disposing risk factors, has led to increased clinical use and pressures on antifungal drugs. This has been exacerbated by a lack of fast, accurate diagnostics that have led treatment guidelines to often recommend preventative strategies in the absence of proven infection, resulting in unnecessary antifungal use in many instances. The consequences of this are multifactorial, but a contribution to emerging drug resistance is of primary concern, with high levels of antifungal use heavily implicated in global shifts to more resistant Candida strains. Preserving and expanding the utility and number of antifungals should therefore be of the highest priority. This may be achievable through the development and use of biomarker tests, bringing about a new era in improved antifungal stewardship, as well as novel antifungals that offer favorable profiles by targeting Candida pathogenesis mechanisms over cell viability.

Outbreak of Cronobacter turicensis in European brown hares (Lepus europaeus).

This is the first report of acute deaths in five European brown hares (Lepus europaeus) attributed to mucoid and necrotizing typhlocolitis caused by genetically different Cronobacter (C.) turicensis strains in northeastern Austria. As this opportunistic pathogen is mainly known for causing disease in immunocompromised humans and neonates, this previously unrecognized potential for a spill over from a wildlife reservoir to humans warrants further attention.

Isolation and identification of emergent multidrug‐resistant Stenotrophomonas maltophilia from skin ulcers of Sarcoptes‐infested pigs

AbstractStenotrophomonas maltophilia is an emergent multidrug‐resistant bacterium. Clinical conditions caused by this bacterium range from skin and soft tissue infection to graver septicaemia and cardiac involvement in immunocompromised humans. A recent whole‐genome analysis corroborates the hypothesis of the potential contribution of animals as reservoirs for human infections, strengthening the possibility of zoonoses. This paper reports the isolation of S. maltophilia from skin ulcers of pigs, associated with sarcoptic mange. Swabs from five pigs with skin ulcers were collected and processed. The cultural, biochemical characterisation and antibiotic susceptibility testing of the isolates were performed. The isolated organisms were found to be of similar cultural morphology and biochemical characteristics. Two representative isolates were subjected to molecular characterisation targeting 16s ribosomal RNA (rRNA). The polymerase chain reaction product was subjected to sequencing followed by basic local alignment search tool analysis, confirming the organism as S. maltophilia. Antibiotic susceptibility testing using 11 different antibiotics revealed that the organism is multidrug resistant with susceptibility towards oxytetracycline and cotrimoxazole.

Enterocytozoon schreckii n. sp. Infects the Enterocytes of Adult Chinook Salmon (Oncorhynchus tshawytscha) and May Be a Sentinel of Immunosenescence.

ABSTRACTA novel Enterocytozoon infection was identified in the intestines of sexually mature Chinook salmon. While microsporidian parasites are common across a diverse range of animal hosts, this novel species is remarkable because it demonstrates biological, pathological, and genetic similarity with Enterocytozoon bieneusi, the most common causative agent of microsporidiosis in AIDS patients. There are similarities in the immune and endocrine processes of sexually mature Pacific salmon and immunocompromised humans, suggesting possible common mechanisms of susceptibility in these two highly divergent host species. The discovery of Enterocytozoon schreckii n. sp. contributes to clarifying the phylogenetic relationships within family Enterocytozoonidae. The phylogenetic and morphological features of this species support the redescription of Enterocytozoon to include Enterospora as a junior synonym. Furthermore, the discovery of this novel parasite may have important implications for conservation, as it could be a sentinel of immune suppression, disease, and prespawning mortality in threatened populations of salmonids.IMPORTANCE In this work, we describe a new microsporidian species that infects the enterocytes of Chinook salmon. This novel pathogen is closely related to Enterocytozoon bieneusi, an opportunistic pathogen commonly found in AIDS patients and other severely immunocompromised humans. The discovery of this novel pathogen is of interest because it has only been found in sexually mature Chinook salmon, which have compromised immune systems due to the stresses of migration and maturation and which share similar pathological features with immunocompromised and senescent humans. The discovery of this novel pathogen could lead to new insights regarding how microsporidiosis relates to immunosuppression across animal hosts.

Detection of Cytokines and Collectins in Bronchoalveolar Fluid Samples of Patients Infected with Histoplasma capsulatum and Pneumocystis jirovecii.

Histoplasmosis and pneumocystosis co-infections have been reported mainly in immunocompromised humans and in wild animals. The immunological response to each fungal infection has been described primarily using animal models; however, the host response to concomitant infection is unknown. The present work aimed to evaluate the pulmonary immunological response of patients with pneumonia caused either by Histoplasma capsulatum, Pneumocystis jirovecii, or their co-infection. We analyzed the pulmonary collectin and cytokine patterns of 131 bronchoalveolar lavage samples, which included HIV and non-HIV patients infected with H. capsulatum, P. jirovecii, or both fungi, as well as healthy volunteers and HIV patients without the studied fungal infections. Our results showed an increased production of the surfactant protein-A (SP-A) in non-HIV patients with H. capsulatum infection, contrasting with HIV patients (p < 0.05). Significant differences in median values of SP-A, IL-1β, TNF-α, IFN-γ, IL-18, IL-17A, IL-33, IL-13, and CXCL8 were found among all the groups studied, suggesting that these cytokines play a role in the local inflammatory processes of histoplasmosis and pneumocystosis. Interestingly, non-HIV patients with co-infection and pneumocystosis alone showed lower levels of SP-A, IL-1β, TNF-α, IFN-γ, IL-18, IL-17A, and IL-23 than histoplasmosis patients, suggesting an immunomodulatory ability of P. jirovecii over H. capsulatum response.

A review of ocularEncephalitozoon cuniculiinfection in the rabbit

Encephalitozoon cuniculi is a microsporidian parasite affecting rabbits and other mammals, including immunocompromised humans. One clinical manifestation of E. cuniculi is the ocular form, which typically presents with phacoclastic uveitis, a yellow-white granuloma and a cataract. This literature review focuses on the aetiopathogenesis, presentation, diagnosis and treatment options for ocular E. cuniculi with emphasis on phacoemulsification, the gold standard treatment.

Ypd1 Is an Essential Protein of the Major Fungal Pathogen Aspergillus fumigatus and a Key Element in the Phosphorelay That Is Targeted by the Antifungal Drug Fludioxonil.

Aspergillus fumigatus is a major fungal pathogen causing life threatening infections in immunocompromised humans and certain animals. The HOG pathway is for two reasons interesting in this context: firstly, it is a stress signaling pathway that contributes to the ability of this pathogen to adapt to various stress conditions and secondly, it is the target of antifungal agents, such as fludioxonil or pyrrolnitrin. In this study, we demonstrate that Ypd1 is an essential protein in A. fumigatus. As the central component of the multistep phosphorelay it represents the functional link between the sensor histidine kinases and the downstream response regulators SskA and Skn7. A GFP-Ypd1 fusion was found to reside in both, the cytoplasm and the nucleus and this pattern was only slightly affected by fludioxonil. A strain in which the ypd1 gene is expressed from a tet-on promoter construct is unable to grow under non-inducing conditions and shows the characteristic features of A. fumigatus wild type hyphae treated with fludioxonil. Expression of wild type Ypd1 prevents this lethal phenotype, but expression of an Ypd1 mutant protein lacking the conserved histidine at position 89 was unable to do so, which confirms that A. fumigatus Ypd1 is a phosphotransfer protein. Generation of ypd1tet-on variants of several mutant strains revealed that the lethal phenotype associated with low amounts of Ypd1 depends on SskA, but not on TcsC or Skn7. The ΔsskA ypd1tet-on, but not the ΔsskAΔskn7 ypd1tet-on mutant, was sensitive to fludioxonil, which underlines the importance of Skn7 in this context. We finally succeeded to delete ypd1, but only if sskA and skn7 were both inactivated, not in a ΔsskA single mutant. Hence, a deletion of ypd1 and an inactivation of Ypd1 by fludioxonil result in similar phenotypes and the two response regulators SskA and Skn7 are involved in both processes albeit with a different relative importance.

The opportunistic intracellular bacterial pathogen Rhodococcus equi elicits type I interferon by engaging cytosolic DNA sensing in macrophages

Rhodococcus equi is a major cause of foal pneumonia and an opportunistic pathogen in immunocompromised humans. While alveolar macrophages constitute the primary replicative niche for R. equi, little is known about how intracellular R. equi is sensed by macrophages. Here, we discovered that in addition to previously characterized pro-inflammatory cytokines (e.g., Tnfa, Il6, Il1b), macrophages infected with R. equi induce a robust type I IFN response, including Ifnb and interferon-stimulated genes (ISGs), similar to the evolutionarily related pathogen, Mycobacterium tuberculosis. Follow up studies using a combination of mammalian and bacterial genetics demonstrated that induction of this type I IFN expression program is largely dependent on the cGAS/STING/TBK1 axis of the cytosolic DNA sensing pathway, suggesting that R. equi perturbs the phagosomal membrane and causes DNA release into the cytosol following phagocytosis. Consistent with this, we found that a population of ~12% of R. equi phagosomes recruits the galectin-3,-8 and -9 danger receptors. Interestingly, neither phagosomal damage nor induction of type I IFN require the R. equi's virulence-associated plasmid. Importantly, R. equi infection of both mice and foals stimulates ISG expression, in organs (mice) and circulating monocytes (foals). By demonstrating that R. equi activates cytosolic DNA sensing in macrophages and elicits type I IFN responses in animal models, our work provides novel insights into how R. equi engages the innate immune system and furthers our understanding how this zoonotic pathogen causes inflammation and disease.

Orbital apex syndrome with frontal abscess secondary to sinusitis due to Candida guilliermondii

Candida guilliermondii is an opportunistic pathogen that rarely causes invasive candidiasis even in immunocompromised humans. We report a case presentation of invasive C. guilliermondii rhinosinusitis causing an orbital and intracranial extension (frontal lobe abscess). An aggressive multidisciplinary team management is a key approach in invasive fungal sinusitis and avoided mortality in this case. When orbital apex syndrome secondary to sinusitis is encountered in an immunocompromised patient, the treating physician should consider fungal infection as a causative agent.

Glucose Decoration on Wall Teichoic Acid Is Required for Phage Adsorption and InlB-Mediated Virulence in Listeria ivanovii.

ABSTRACTListeria ivanovii (Liv) is an intracellular Gram-positive pathogen that primarily infects ruminants but also occasionally causes enteric infections in humans. Albeit rare, this bacterium possesses the capacity to cross the intestinal epithelium of humans, similar to its more frequently pathogenic cousin, Listeria monocytogenes (Lmo). Recent studies in Lmo have shown that specific glycosyl modifications on the cell wall-associated glycopolymers (termed wall teichoic acid [WTA]) of Lmo are responsible for bacteriophage adsorption and retention of the major virulence factor internalin B (InlB). However, the relationship between InlB and WTA in Liv remains unclear. Here, we report the identification of the unique gene liv1070, which encodes a putative glucosyltransferase in the polycistronic WTA gene cluster of the Liv WSLC 3009 genome. We found that in-frame deletion of liv1070 led to loss of the glucose substitution on WTA, as revealed by ultraperformance liquid chromatography–mass spectrometry (UPLC-MS) analysis. Interestingly, the glucose-deficient mutant became resistant to phage B025 infection due to an inability of the phage to adsorb to the bacterial surface, a binding process mediated by the receptor-binding protein B025_Gp17. As expected, deletion of liv1070 led to loss of InlB retention on the bacterial cell wall, which corresponded to a drastic decrease in cellular invasion. Genetic complementation of liv1070 restored the characteristic phenotypes, including glucose decoration, phage adsorption, and cellular invasion. Taken together, our data demonstrate that an interplay between phage, bacteria, and host cells also exists in Listeria ivanovii, suggesting that the trade-off between phage resistance and virulence attenuation may be a general feature in the genus Listeria.IMPORTANCE Listeria ivanovii is a Gram-positive bacterial pathogen known to cause enteric infection in rodents and ruminants and occasionally in immunocompromised humans. Recent investigations revealed that in its better-known cousin Listeria monocytogenes, strains develop resistance to bacteriophage attack due to loss of glycosylated surface receptors, which subsequently results in disconnection of one of the bacterium's major virulence factors, InlB. However, the situation in L. ivanovii remains unclear. Here, we show that L. ivanovii acquires phage resistance following deletion of a unique glycosyltransferase. This deletion also leads to dysfunction of InlB, making the resulting strain unable to invade host cells. Overall, this study suggests that the interplay between phage, bacteria, and the host may be a feature common to the genus Listeria.

Zoonotic potential of Newcastle disease virus: Old and novel perspectives related to public health.

Newcastle disease virus (NDV) has a worldwide distribution, causing lethal infection in a wide range of avian species. Affected birds develop respiratory, digestive and neurologic symptoms with profound immunosuppression. Mild systemic Newcastle disease (ND) infection restricted to the respiratory and neurological systems can be observed in humans and other non-avian hosts. Evidence of ND infection and its genome-based detection have been reported in Bovidae (cattle and sheep), Mustelidae (mink), Cercetidae (hamster), Muridae (mice), Leporidae (rabbit), Camelidae (camel), Suidae (pig), Cercophithecidae (monkeys) and Hominidae (humans). Owing to frequent ND outbreaks in poultry workers, individuals engaged in the veterinary field, including poultry production or evisceration and vaccine production units have constantly been at a much higher risk than the general population. A lethal form of infection has been described in immunocompromised humans and non-avian species including mink, pig and cattle demonstrating the capability of NDV to cross species barriers. Therefore, contact with infectious material and/or affected birds can pose a risk of zoonosis and raise public health concerns. The broad and expanding host range of NDV and its maintenance within non-avian species hampers disease control, particularly in disease-endemic settings.

Detection and antibiogram of Edwardsiella tarda from Oreochromis niloticus (Tilapia fish) obtained from selected farms in Ibadan, Nigeria

Edwardsiellosis caused by Edwardsiella tarda is a septicemic bacterial disease responsible for 5- 70% mortalities and prevalence up-to 70% in freshwater fishes. Although rarely associated with human infections, Edwardsiella tarda have been found to cause gastroenteritis, soft tissue infection, liver abscess, tubo-ovarian abscess, and mycotic aneurysm mostly in immunocompromised humans. This study investigated prevalence and antibiogram of E. tarda isolated from Oreochromis niloticus obtained from selected farms in Ibadan, Nigeria. A total of 156 samples consisting: gills, intestines and skins were collected from 52 O. niloticus from Egbeda-(A), Ido-(B), Ibadan: NorthEast-(C) and North-West-(D) for bacteriological analysis. E. tarda Isolation, identification, and antibiogram were performed using standard methods. Data were analyzed using Chi-Square. An overall prevalence of 62.5% was observed for E. tarda with 87.5%, 62.5% and 50.0% for gills, intestine and skin samples, respectively, whilst overall location prevalence were observed as: 100.0%-(A), 50.0%-(B), 66.6%-(C) and 50.0%-(D). Isolates exhibited resistance patterns comprising; 100.0%-(Ceftazidime-(CPZ), Cefuroxime-(CRX) and Meropenem-(MEM)), 91.7%- Cefotaxime-(CTX), 83.3%-(Tetracyclin-(TET)), 50.0%-(Cotrimoxazole-(COT)), 33.3% (Ceftriaxone-(CTR) and Gentamicin-(GEN)), 25.0%-(Chloramphenicol-(CHL)), 16.7%-Amikacin- (AMK) and 8.3%-(Ciprofloxacin-(CIP)). Multi-drug resistance pattern: CRX-CFZ-MEM-(100%), CRX-CTR-CTX-CFZ-MEM-(83.3%), CRX-CTR-CTX-CFZ-MEM-TET-(66.7%), CRX-CTRCTX-CFZ-MEM-TET-COT-(58.3%) and CRX-CTR-CTX-CFZ-MEM-TET-COT-GEN-(8.3%) was observed. Isolation and identification of E. tarda from O. niloticus confirm its presence in Ibadan and affirms that O. niloticus harbors, and could serve as a source of infection to humans. The antimicrobial resistance patterns of isolates to antibiotics indicate misuse in aquaculture and indiscriminate disposal of antibiotics into aquatic environments. This suggests risks of transmission of infectious agents to human and probable spread of resistant pathogens to humans from the environment.

Helicobacter canis bacteraemia in a rheumatoid arthritis patient treated with tofacitinib: case report and literature review

BackgroundNon-Helicobacter pylori species (NHPS) are newly emerging bacteria that naturally inhabit birds and mammals apart from humans and rarely cause diseases in humans. In recent years, a rise in the number of cases associated with NHPS infections in humans has been observed. Among them, infections with Helicobacter (H.) canis are sporadic and challenging to recognise clinically. To date, ten cases of H. canis infections in mainly immunocompromised humans have been reported in the literature. Transmission pathway is most likely zoonotic via the faecal-oral route during close contacts with dogs and cats or may result from a contaminated sheep milk intake. No clear guidelines for successful antibiotic regimen are known. Important additional risk factor for infection might be biologic agents and Janus kinase inhibitors (JAKi) used in the treatment of rheumatoid arthritis (RA) and other conditions. Herein we present the first case of H. canis bacteraemia in a RA patient treated with novel JAKi tofacitinib.Case presentationA 65-year-old female patient with RA and rituximab-induced hypogammaglobulinemia treated with tofacitinib, methotrexate, and methylprednisolone came to a planned visit in our outpatient rheumatology clinic. She presented with a history of back pain that significantly worsened 2 days before visit. She had numbness and tingling sensation in both legs and muscle weakness. Neurological examination was within a normal range. The patient was afebrile, had no chills, and was haemodynamically stable. She was in close contact with her pet dogs. Laboratory examination showed increased markers of inflammation. She was found to have H. canis bacteraemia with underlying multilevel degenerative lumbar spinal stenosis. Identification of H. canis was performed by MALDI-TOF MS and 16 S rRNA gene sequence analysis of isolate from subcultured positive aerobic blood culture bottles. Antimicrobial susceptibility testing showed low minimum inhibitory concentrations to amoxicillin-clavulanate, cefotaxime, ceftriaxone, meropenem, and gentamicin. She was treated with combined antibiotic regimen (ceftriaxone, doxycycline) for 14 days, which resulted in total remission of the infection.ConclusionsClinicians should recognise H. canis infection risk in patients with recent pet exposure and predisposing factors such as immunodeficiency disorders or diseases that demand immunosuppressive drug therapy. A minimum of two weeks of antibiotic therapy is suggested.

‘The Good, the Bad and the Ugly’ in the shades of green: the genus Trichoderma in the spotlight

The ascomycetous filamentous fungal genus Trichoderma has at least two faces, like Agni, the God of fire in Hindu mythology. Or maybe even three? The ‘Good’, the ‘Bad’ and the ‘Ugly’? In fact, Trichoderma species can be considered: (1) ‘Good’—as plant-beneficial microorganisms in agriculture due to a plethora of antagonistic mechanisms acting against plant pathogens, e.g., inhibiting them through the production of antimicrobial metabolites or by direct parasitism, or indirectly, promoting the growth of crop plants and inducing their immune system; (2) ‘Bad’ —as devastating agents of green mould diseases in the cultivation of mushrooms viz. champignon, oyster mushroom, shiitake, etc., destroying crops and thereby causing serious economic damage world-wide; and (3) ‘Ugly’—as opportunistic pathogens of mainly immunocompromised humans. Do biocontrol Trichoderma strains represent a risk to mushroom production or human health? Is the agricultural application of Trichoderma strains safe or rather risky? The aim of this review is to address these important questions.

Antibody-guided in vivo imaging of Aspergillus fumigatus lung infections during antifungal azole treatment

Invasive pulmonary aspergillosis (IPA) is a life-threatening lung disease of immunocompromised humans, caused by the opportunistic fungal pathogen Aspergillus fumigatus. Inadequacies in current diagnostic procedures mean that early diagnosis of the disease, critical to patient survival, remains a major clinical challenge, and is leading to the empiric use of antifungal drugs and emergence of azole resistance. A non-invasive procedure that allows both unambiguous detection of IPA and its response to azole treatment is therefore needed. Here, we show that a humanised Aspergillus-specific monoclonal antibody, dual labelled with a radionuclide and fluorophore, can be used in immunoPET/MRI in vivo in a neutropenic mouse model and 3D light sheet fluorescence microscopy ex vivo in the infected mouse lungs to quantify early A. fumigatus lung infections and to monitor the efficacy of azole therapy. Our antibody-guided approach reveals that early drug intervention is critical to prevent complete invasion of the lungs by the fungus, and demonstrates the power of molecular imaging as a non-invasive procedure for tracking IPA in vivo.

Emerging Human Babesiosis with "Ground Zero" in North America.

The first case of human babesiosis was reported in the literature in 1957. The clinical disease has sporadically occurred as rare case reports in North America and Europe in the subsequent decades. Since the new millennium, especially in the last decade, many more cases have apparently appeared not only in these regions but also in Asia, South America, and Africa. More than 20,000 cases of human babesiosis have been reported in North America alone. In several cross-sectional surveys, exposure to Babesia spp. has been demonstrated within urban and rural human populations with clinical babesiosis reported in both immunocompromised and immunocompetent humans. This review serves to highlight the widespread distribution of these tick-borne pathogens in humans, their tick vectors in readily accessible environments such as parks and recreational areas, and their phylogenetic relationships.

Rhodococcus infection in HIV infected patients: Clinical presentation and diagnoses

Background: Rhodococcus Equi is a gram positive coryneform bacterium that causes zoonotic infections in the animal kingdom and ias been reported in immunocompromised humans as emerging opportunistic pathogens. Methods & Materials: Retrospective review of patients electronic records from y 2006 to 2011, that were microbiologically confirmed rhodococcus equi infection. Results: A total of 26 patients were HIV positive with a median CD4 ount of 14 cells/ul.Mode of hiv transmission were 40.7% injecting drug use (11 patients), 51.7% sexual contact and 7.6% were unknown. None of the patients had a known history of contact with any animal sources for rhodococcus. 70.4%(19) patients were antiretroviral naïve at the time of presentation, 48%(13) patients had other concurrent AIDS defining illnesses. Pulmonary involvement with confirmed bacteraemia was seen in 77.8% (21) cases.18.5% (5) had primary bacteraemia with no other source of infection. One patient had isolated right suppurative lymphadenitis. Cavitatory pneumonia were seen in majority of the cases. In comparison to the available literature data, we saw a similar sensitivity pattern for most of our isolates with a resistance towards penicillin and ampicillin. Most patients were treated with a combination of antibiotics Conclusion: Increase awareness of rhodococcus infection as an opportunistic pathoegn,prompt microbiological diagnosis and combined antimicrobial treatment seem to be the cornerstone pf effective treatment. Early initiation of antiretroviral treatment and adherence seem to be necessary to improve outcome.

Aspergillus fumigatus G-Protein Coupled Receptors GprM and GprJ Are Important for the Regulation of the Cell Wall Integrity Pathway, Secondary Metabolite Production, and Virulence.

G-protein coupled receptors (GPCRs) are extracellular signaling receptors that sense environmental cues. Fungi sense their environment primarily through GPCR-mediated signaling pathways, which, in turn, regulate fungal development, metabolism, virulence, and mycotoxin biosynthesis. Aspergillus fumigatus is an important human pathogen that causes aspergillosis, a heterogeneous group of diseases that present a wide range of clinical manifestations. Here, we investigate in detail the role of the GPCRs GprM and GprJ in growth and gene expression. GprM and GprJ are important for melanin production and the regulation of the cell wall integrity (CWI) pathway. Overexpression of gprM and gprJ causes a 20 and 50% reduction in growth rate compared to the wild-type (WT) strain and increases sensitivity to cell wall-damaging agents. Phosphorylation of the CWI protein kinase MpkA is increased in the ΔgprM and ΔgprJ strains and decreased in the overexpression mutants compared to the WT strain. Furthermore, differences in cell wall polysaccharide concentrations and organization were observed in these strains. Transcriptome sequencing suggests that GprM and GprJ negatively regulate genes encoding secondary metabolites (SMs). Mass spectrometry analysis confirmed that the production of fumagillin, pyripyropene, fumigaclavine C, fumiquinazoline, and fumitremorgin is reduced in the ΔgprM and ΔgprJ strains, at least partially through the activation of MpkA. Overexpression of grpM also resulted in the regulation of many transcription factors, with AsgA predicted to function downstream of GprM and MpkA signaling. Finally, we show that the ΔgprM and ΔgprJ mutants are reduced in virulence in the Galleria mellonella insect model of invasive aspergillosis.IMPORTANCEA. fumigatus is the main etiological agent of invasive pulmonary aspergillosis, a life-threatening fungal disease that occurs in severely immunocompromised humans. Withstanding the host environment is essential for A. fumigatus virulence, and sensing of extracellular cues occurs primarily through G-protein coupled receptors (GPCRs) that activate signal transduction pathways, which, in turn, regulate fungal development, metabolism, virulence, and mycotoxin biosynthesis. The A. fumigatus genome encodes 15 putative classical GPCRs, with only three having been functionally characterized to date. In this work, we show that the two GPCRs GprM and GprJ regulate the phosphorylation of the mitogen-activated protein kinase MpkA and thus control the regulation of the cell wall integrity pathway. GprM and GprJ are also involved in the regulation of the production of the secondary metabolites fumagillin, pyripyropene, fumigaclavine C, fumiquinazoline, melanin, and fumitremorgin, and this regulation partially occurs through the activation of MpkA. Furthermore, GprM and GprJ are important for virulence in the insect model Galleria mellonella This work therefore functionally characterizes two GPCRs and shows how they regulate several intracellular pathways that have been shown to be crucial for A. fumigatus virulence.

Route-coupled pathogenicity and immunogenicity of vaccinia virus variant inoculated mice

Vaccinia virus had played a key role in the global smallpox eradication. However, in case of mass vaccination with various Vaccinia virus strains severe side effects were revealed sometimes ending up with lethal outcomes, especially in immunocompromised humans. Hence, in 1980 the World Health Organization recommended to cancel smallpox vaccination after declaring about smallpox eradication. Over the last 40 years, human population virtually lost immunity not only against smallpox, but also against other zoonotic orthopoxvirus infections, such as monkeypox, cowpox, buffalopox, and camelpox. All of them pose a represent increasing threat to human health and heighten a risk of emerging highly contagious viruses due to natural evolution of previous zoonotic orthopoxviruses. In order to prevent development of small outbreaks into spreading epidemics and, thus, to decrease a risk of emergence due to natural evolution of highly pathogenic for humans orthopoxviruses, efforts should be applied to develop safe new generation live vaccines based on Vaccinia virus with target virulence genes inactivation. These strains should be examined in laboratory animal models inoculated via different routes. Currently, Vaccinia virus often becomes attenuated to create live recombinant vaccines due to inserting target DNA sequences into the virus virulence genes resulting in their inactivation. Vaccinia virus strain LIVP used in the Russian Federation as smallpox vaccine as well as derivative attenuated variant LIVP-GFP created by using genetic engineering methods with inactivating its thymidine kinase gene were examined. Such viruses were intracerebrally inoculated into suckling mice at doses of 101 or 102 PFU/animal for neurovirulence assessment. Adult mice were infected intranasally, subcutaneously or intradermally at doses of 107 or 108 PFU/animal and clinical manifestations were analyzed for 14 days. On the 28th day after the onset, blood serum samples were collected from individual mice to measure virus specific antibody level by using ELISA. It was shown that recombinant Vaccinia virus strain LIVP-GFP displayed markedly lowered neurovirulence and pathogenicity for mice as compared to parental LIVP. Finally, intradermal route turned out to demonstrate the most safe and effective profile for immunization with both examined Vaccinia virus strains.

First Demonstration of Clinical Fusarium Strains Causing Cross-Kingdom Infections from Humans to Plants.

Mycotoxins from the Fusarium genus are widely known to cause economic losses in crops, as well as high mortalities rates among immunocompromised humans. However, to date, no correlation has been established for the ability of Fusarium to cause cross-kingdom infection between plants and humans. The present investigation aims to fill this gap in the literature by examining cross-kingdom infection caused by Furasium strains isolated from non-immunocompromised or non-immunosuppressed humans, which were subsequently reinfected in plants and on human tissue. The findings document for the first time cross-kingdom infective events in Fusarium species, thus enhancing our existing knowledge of how mycopathogens continue to thrive in different hosts.