Adenoviruses are increasingly recognized as contributors to morbidity and mortality among stem cell and solid-organ transplant recipients. Clinical presentations range from asymptomatic viremia to respiratory and gastrointestinal disease, hemorrhagic cystitis, and severe disseminated illness. The limited clinical data available support the use of cidofovir for many of these illnesses. Prospective studies are needed to better understand the pathogenesis of and therapeutic options for adenoviral infections in this patient population.

Adenovirus Infections in Transplant Recipients

Chronic spirochetal infection can cause slowly progressive dementia, cortical atrophy and amyloid deposition in the atrophic form of general paresis. There is a significant association between Alzheimer disease (AD) and various types of spirochete (including the periodontal pathogen Treponemas and Borrelia burgdorferi), and other pathogens such as Chlamydophyla pneumoniae and herpes simplex virus type-1 (HSV-1). Exposure of mammalian neuronal and glial cells and organotypic cultures to spirochetes reproduces the biological and pathological hallmarks of AD. Senile-plaque-like beta amyloid (Aβ) deposits are also observed in mice following inhalation of C. pneumoniae in vivo, and Aβ accumulation and phosphorylation of tau is induced in neurons by HSV-1 in vitro and in vivo. Specific bacterial ligands, and bacterial and viral DNA and RNA all increase the expression of proinflammatory molecules, which activates the innate and adaptive immune systems. Evasion of pathogens from destruction by the host immune reactions leads to persistent infection, chronic inflammation, neuronal destruction and Aβ deposition. Aβ has been shown to be a pore-forming antimicrobial peptide, indicating that Aβ accumulation might be a response to infection. Global attention and action is needed to support this emerging field of research because dementia might be prevented by combined antibiotic, antiviral and anti-inflammatory therapy.

/pdf/emerging-roles-of-pathogens-in-alzheimer-disease-5digrqjmtt.pdf

Emerging roles of pathogens in Alzheimer disease

Human adenoviruses (HAdV) are responsible for a wide spectrum of diseases. The neutralization e determinant (loops 1 and 2) and the hemagglutination γ determinant are relevant for the taxonomy of HAdV. Precise type identification of HAdV prototypes is crucial for detection of infection chains and epidemiology. e and γ determinant sequences of all 51 HAdV were generated to propose molecular classification criteria. Phylogenetic analysis of e determinant sequences demonstrated sufficient genetic divergence for molecular classification, with the exception of HAdV-15 and HAdV-29, which also cannot be differentiated by classical cross-neutralization. Precise sequence divergence criteria for typing (

https://jvi.asm.org/content/jvi/79/24/15265.full.pdf

Phylogenetic analysis of the main neutralization and hemagglutination determinants of all human adenovirus prototypes as a basis for molecular classification and taxonomy.

Adenovirus (ADV) was first associated with severe morbidity and mortality in bone marrow transplant recipients in 1985. Numerous reports since then have confirmed the importance of ADV in recipients of hematopoietic stem cell transplants (HSCT). The immunosuppression involved with solid organ transplantation (SOT) also predisposes recipients to severe initial or reactivation ADV infections. This chapter describes the emerging importance of ADV in both HSCT and SOT recipients. A retrospective review of pediatric liver transplant recipients noted infection in 10%, with evidence of invasive disease occurring in 4.1%; most disease occurred in the immediate posttransplant period. Nuclear enlargement and intranuclear inclusions develop and contain adenovirions as seen by electron microscopy. Immunohistochemistry and in situ hybridization (technically challenging and not widely available) may further improve the sensitivity over that of histopathology and may be particularly helpful in differentiating rejection from ADV disease, particularly among small bowel transplant recipients. Treatment of ADV in HSCT and SOT recipients can be broken down into two major issues: whom to treat and how best to treat them. A wide variety of antiviral drugs have been used to treat ADV disease. Vidarabine has limited availability and significant toxicity but may have a role in the management of hemorrhagic cystitis. At present, only cidofovir appears to have significant antiviral efficacy. Future treatment strategies might include analogs of cidofovir and ex vivo generation of ADV-specific cytotoxic T cells with subsequent transplantation into patients suffering from or at high risk for ADV disease.

Adenoviral Infections in Transplant Recipients

There is growing evidence of higher prevalence of chronic obstructive pulmonary disease (COPD) in the elderly. Age-associated changes in the structure and function of the lung may increase a pathogenetic susceptibility to COPD. The lung may directly develop COPD in old age. Suitable animal models are required to test this hypothesis. Senescence-accelerated mice (SAM), Klotho gene depleted mice, and SMP-30 knockout mice were investigated with their short lifespan associated with premature aging in systemic organs. The structural and physiological changes demonstrated senile lung, not emphysema, without alveolar wall destruction. Tobacco smoke exposure resulted in the development of emphysema. These findings support the hypothesis that premature aging is not the direct cause of emphysema, but that premature aging enhances the susceptibility of the lung to extrinsic insults including tobacco smoke in these animal models. The mechanism of this enhancement needs further investigation and its elucidation should advance COPD management.

The aging lung and chronic obstructive pulmonary disease: similarity and difference.

This study examined age-related biochemical changes of the lung in an animal model of senile lung, senescence-accelerated mouse (SAM). Bronchoalveolar lavage (BAL) was performed on two strains of SAM, the senescence-prone strain (SAM P2) and the senescence-resistant strain (SAM R1), as well as on normal ageing C57 black mice (C57BL), aged 1-24 months. Elastase-like and elastase inhibitory activity of BAL fluid (BALF), glutathione (GSH) and oxidized GSH (GSSG) content both of BALF and lung tissue, and oxygen radical generation of free lung cells obtained by BAL were examined in the three strains of mice. Cell populations did not change throughout the life in SAM strains and C57BL. The elastolytic activity in SAM was greater than in C57BL, but there was no change with age. Both a decreased content of GSH and an increased oxidation of the GSH in BALF were markedly observed with ageing in SAM P2. In the lung tissue, the GSSG/GSH ratio in SAM strains was consistently greater than that in C57BL, suggesting that the GSH redox cycle of the lung may be impaired in SAM strains. The oxygen radical generation by free lung cells increased with age in all three strains, but the increase was earlier and more pronounced in SAM P2 than in the other two strains. In conclusion, an impaired GSH redox cycle and an increased formation of oxygen radicals are observed in the lungs of SAM with increasing age.

https://erj.ersjournals.com/content/erj/8/3/450.full.pdf

Biochemical characteristics of lungs in senescence-accelerated mouse (SAM)

We studied the influences of inhaled tobacco smoke on lung structure, biochemical changes in bronchoalveolar lavage (BAL) fluid, and glutathione (GSH) content of the lung in the senescence accelerated mouse (SAM), using 30 female SAM-P/8 as the "senescence-prone series", compared with SAM-R/1 as the "senescence-resistant series". At 18 wks of age, half of each series were housed in Hamburg II machines and exposed to an atmosphere of tobacco smoke for 5 wks, 10 min a day, 5 days a wk. At 24 wks of age, all of the animals were sacrificed. Blood, lung, liver, kidney and eyes were removed and the contents of GSH and thiol group (-SH) were measured (n = 5). We also performed BAL, to determine its total protein, albumin, and fibronectin contents, and elastase-like activity, elastase inhibitory capacity (EIC), and trypsin inhibitory capacity (TIC) (n = 5). Histological changes of the lungs from non-lavaged animals were also examined by light microscopy (n = 5). In SAM-P/8 not exposed to tobacco smoke, the mean linear intercept was longer than that in SAM-R/1. The exposure of SAM-P/8 to tobacco smoke caused increases in its lung weight and the ratio of albumin to total protein in BAL fluid, a decrease in the EIC/TIC ratio in BAL fluid, and a decrease in the GSH content and the GSH/-SH ratio of the lung, compared with those not exposed. We also observed focal infiltration of macrophages into alveoli with hyaline membrane and thickened alveolar wall in SAM-P/8 with tobacco exposure.(ABSTRACT TRUNCATED AT 250 WORDS)

https://erj.ersjournals.com/content/erj/3/9/1029.full.pdf

Influences of inhaled tobacco smoke on the senescence accelerated mouse (SAM).

AIMS--To investigate adenovirus pulmonary infections in bone marrow transplant (BMT) recipients. METHODS--Formalin fixed, paraffin wax embedded lung tissue was examined from 13 necropsy cases after BMT using PCR and in situ hybridisation to detect adenovirus DNA. The E1A region of the adenoviral genome was targeted for PCR. In situ hybridisation was performed only in the PCR positive cases. RESULTS--Of the 13 lung specimens analysed, nine cases were negative for adenoviral nucleic acid. Four (30%) PCR and two (15%) in situ hybridisation positive cases were found. In some of the patients there were clinical and pathological indications that some diseases might be associated with adenovirus infection--haemorrhagic cystitis (three cases); necrotising pneumonia (one case). In necrotising pneumonia in which no pathogenic agents had been shown by conventional histological study, the in situ hybridisation technique showed positive staining for adenovirus. In a patient who died of renal failure caused by adenovirus nephritis, both PCR and in situ hybridisation were positive in the lung as well as in the kidney, although no histological change was found. Two PCR positive cases lacked positive sites for adenovirus by in situ hybridisation. CONCLUSIONS--The combination of PCR and in situ hybridisation could be useful for diagnosing adenovirus infection of the lung in BMT recipients. These results provide a basis for exploring further the clinical use of PCR and in situ hybridisation to diagnose adenovirus infection.

https://jcp.bmj.com/content/jclinpath/47/11/973.full.pdf

Adenovirus pulmonary infections identified by PCR and in situ hybridisation in bone marrow transplant recipients.

To investigate whether brain tissue is infected latently by adenovirus via a monocyte/microglia-mediated entry mechanism, brain tissue resected at necropsy from seven senile subjects (five with senile dementia of Alzheimer type (SDAT) and two subjects without pathological changes) was examined for adenovirus early region 1A (E1A) gene and its expression using in situ hybridisation and immunohistochemical staining. HLA-DR positive, reactive microglial cells in both SDAT and normal brain tissue showed positive hybridisation and immunoreactive expression of adenovirus E1A. Thus there may be monocyte/microglia-mediated entry of adenovirus in the central nervous system which would be a novel and presumably common interaction between brain tissue and adenovirus.

https://jcp.bmj.com/content/jclinpath/47/3/275.full.pdf

Immunohistochemical and in situ hybridisation detection of adenovirus early region 1A (E1A) gene in the microglia of human brain tissue.

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Biochemical characteristics of lungs in senescence-accelerated mouse (SAM)

Influences of inhaled tobacco smoke on the senescence accelerated mouse (SAM).

Adenovirus pulmonary infections identified by PCR and in situ hybridisation in bone marrow transplant recipients.

Immunohistochemical and in situ hybridisation detection of adenovirus early region 1A (E1A) gene in the microglia of human brain tissue.