Pathogenesis Of Opportunistic Infections Research Articles

A three-dimensional immunocompetent intestine-on-chip model as in vitro platform for functional and microbial interaction studies

Alterations of the microbial composition in the gut and the concomitant dysregulation of the mucosal immune response are associated with the pathogenesis of opportunistic infections, chronic inflammation, and inflammatory bowel disease. To create a platform for the investigation of the underlying mechanisms, we established a three-dimensional microphysiological model of the human intestine. This model resembles organotypic microanatomical structures and includes tissue resident innate immune cells exhibiting features of mucosal macrophages and dendritic cells. The model displays the physiological immune tolerance of the intestinal lumen to microbial-associated molecular patterns and can, therefore, be colonised with living microorganisms. Functional studies on microbial interaction between probiotic Lactobacillus rhamnosus and the opportunistic pathogen Candida albicans show that pre-colonization of the intestinal lumen of the model by L. rhamnosus reduces C. albicans-induced tissue damage, lowers its translocation, and limits fungal burden. We demonstrate that microbial interactions can be efficiently investigated using the in vitro model creating a more physiological and immunocompetent microenvironment. The intestinal model allows a detailed characterisation of the immune response, microbial pathogenicity mechanisms, and quantification of cellular dysfunction attributed to alterations in the microbial composition.

Anti-cytokine autoantibodies are associated with opportunistic infection in patients with thymic neoplasia

AbstractPatients with thymic malignancy have high rates of autoimmunity leading to a variety of autoimmune diseases, most commonly myasthenia gravis caused by anti-acetylcholine receptor autoantibodies. High rates of autoantibodies to cytokines have also been described, although prevalence, spectrum, and functionality of these anti-cytokine autoantibodies are poorly defined. To better understand the presence and function of anti-cytokine autoantibodies, we created a luciferase immunoprecipitation system panel to search for autoantibodies against 39 different cytokines and examined plasma from controls (n = 30) and patients with thymic neoplasia (n = 17). In this screen, our patients showed statistically elevated, but highly heterogeneous immunoreactivity against 16 of the 39 cytokines. Some patients showed autoantibodies to multiple cytokines. Functional testing proved that autoantibodies directed against interferon-α, interferon-β, interleukin-1α (IL-1α), IL-12p35, IL-12p40, and IL-17A had biologic blocking activity in vitro. All patients with opportunistic infection showed multiple anti-cytokine autoantibodies (range 3-11), suggesting that anti-cytokine autoantibodies may be important in the pathogenesis of opportunistic infections in patients with thymic malignancy. This study was registered at http://clinicaltrials.gov as NCT00001355.

Polymorphisms in Toll-like receptor genes and susceptibility to infections in allogeneic stem cell transplantation

Discovery of genetic variations in the genes encoding for Toll-like receptors (TLRs) has highlighted a potential link between genomic variation of the host and susceptibility to infections. We investigated the association between polymorphisms in the TLR2, TLR4, and TLR9 genes in recipients of allogeneic hematopoietic stem cell transplant and susceptibility to infections caused by cytomegalovirus and filamentous fungi. A significant association was observed between the presence of the T-1237C polymorphism (TLR9) and susceptibility to viral pneumonia (p=0.04; odds ratio [OR]: 1.73). For fungi, a significant association was observed between the presence of the cosegregating Asp299Gly/Thr399Ile polymorphisms (TLR4) and fungal colonization (p=0.003; OR: 10.6). However, susceptibility to fungal infections, predominantly fungal pneumonia, was instead significantly decreased in the presence of the same polymorphisms (p=0.03; OR: 0.23). Thus, fungal colonization may not predict susceptibility to infection in the presence of these single nucleotide polymorphisms. The finding that defective viral but not fungal sensing may predict susceptibility to infection highlights the divergent function of TLRs in the pathogenesis of opportunistic infections.

Severe conidiobolomycosis complicating induction chemotherapy in a patient with acute lymphoblastic leukaemia

The patient, a 20-year-old male, was a full-time soldier and actively involved in field training when diagnosed with acute lymphoblastic leukaemia. Induction chemotherapy, consisting of vincristine, cyclophosphamide, adriamycin and dexamethasone, was given together with itraconazole 200 mg q.i.d. as fungal prophylaxis. He became neutropenic 13 d after commencing chemotherapy and on d15, developed acute onset of right facial and cervical swelling associated with stridor, which required endoscopic-guided intubation to protect his airways. A contrast-enhanced computed tomography (top left) showed the presence of a large right paratonsillar abscess with inflammatory response extending to the right masseter and parotid spaces, resulting in airway obstruction. He subsequently developed a collapse of the entire left lung because of an obstructive plaque in the left main stem bronchus (top right). A bronchoscopic biopsy of the lesion was initially suggestive of aspergillus tracheobronchitis and empirical treatment with caspofungin was commenced, as the concomitant occurrence of acute renal failure and ischemic hepatitis precluded the use of amphotericin or voriconazole. The patient made a striking recovery and was extubated 4 d later with an associated recovery of neutrophils. However, the correct diagnosis was only established when the causative organism was identified as Conidiobolus coronatus. Microscopically (bottom), sporangiola producing secondary multiplicative spores were seen. Conidiobolus coronatus is a saprophyte in soil or organic debris in a tropical environment and typically causes localized nasal and soft tissue infections in animals and rarely in humans. There is still no consensus on the most appropriate anti-fungal treatment. The social background of a patient may play an important role in the pathogenesis of opportunistic infections in an immunocompromised host.

Pneumopathies alvéolo-interstitielles aiguës chez des patients VIH négatif traités par chimiothérapie anticancéreuse

Introduction. – Treatment of malignant tumors can delay some opportunistic infections. In this paper, we report three cases of alveolo-interstitial pneumonia among HIV negative patients who received chemotherapy. Exegesis. – All three patients received corticotherapy for a long time. In two cases, it was pneumocystis-tuberculosis coinfection. Evolution was favourable for two patients with sulfaméthoxazole-triméthoprime (one with corticotherapy). Conclusion . – The possible role of chemotherapy, corticotherapy and malignant tumor in the pathogenesis of opportunistic infections will be discussed.

Encapsulation of Coagulase-Negative Staphylococci

It is becoming clear that encapsulation is frequent among coagulase negative staphylococci and is unrelated to the formation of extracellular polysaccharide slime by many strains. Crude slime may contain capsular polysaccharides or proteins, as well as cell wall components, but this is probably the result of cell wall turnover in growing bacteria. As in coagulase-positive staphylococci the capsules confer resistance to phagocytosis and can be regarded as important virulence factors. The observation that within the species S. epidermidis several different capsular types can be distinguished serologically suggests the possibility of using the presence and serotype of capsule for biotyping. There is a great need for detailed structural studies of capsular polysaccharides and for the investigation of the role of proteins in the capsules. Several published analyses fail to account for substantial proportions of the weight of isolated capsular material, indicating the presence of components yet to be recognised. Preliminary studies have revealed interesting biological activities of capsular components in humans and experimental animals and further work is likely to provide important new information about the pathogenesis of opportunistic infections by this group of bacteria.

Opportunistic infections in acquired immune deficiency syndrome result from synergistic defects of both the natural and adaptive components of cellular immunity.

We evaluated the cellular immunity of 408 clinically stratified subjects at risk for acquired immune deficiency syndrome (AIDS), to define the role of interferon-alpha production deficits in the pathogenesis of opportunistic infections (OI). We followed 115 prospectively for up to 45 mo. Onset of OI was associated with, and predicted by, deficiency both of interferon-alpha generation in vitro, and of circulating Leu-3a+ cells. Interferon-alpha production is an index of the function of certain non-T, non-B, large granular lymphocytes (LGL) that are independent of T cell help. Leu-3a+ cell counts are a marker of T cell function. OI did not usually develop until both of these mutually independent immune functions were simultaneously critically depressed, leading to a synergistic interaction. These data suggest that the AIDS virus affects a subset of LGL, and that cytokine production by these cells is an important component of the host defense against intracellular pathogens that becomes crucial in the presence of severe T cell immunodeficiency.