Low-Level Expression of the E1B 20-Kilodalton Protein by Adenovirus 14p1 Enhances Viral Immunopathogenesis.

Adenovirus 14p1 (Ad14p1) is an emergent variant of Ad serotype 14 (Ad14) that has caused increased severity of respiratory illnesses during globally distributed outbreaks, including cases of acute respiratory distress syndrome and death. We found that human cell infection with Ad14p1 results in markedly decreased expression of the E1B 20-kilodalton (20K) protein compared to that with infection with wild-type (wt) Ad14. This reduced Ad14p1 E1B 20K expression caused a loss-of-function phenotype of Ad-infected cell corpses that, in contrast to cells infected with wt Ad14, either failed to repress or increased NF-κB-dependent, proinflammatory cytokine responses of responder human alveolar macrophages. A small-animal model of Ad14-induced lung infection was used to test the translational relevance of these in vitro observations. Intratracheal infection of Syrian hamsters with Ad14p1 caused a marked, patchy bronchopneumonia, whereas hamster infection with wt Ad14 caused minimal peribronchial inflammation. These results suggest that this difference in E1B 20K gene expression during Ad14p1 infection and its modulating effect on the interactions between Ad14-infected cells and the host innate immune response could explain the increased immunopathogenic potential and associated increase in clinical illness in some people infected with the Ad14p1 outbreak strain.IMPORTANCE We previously reported that Ad-infected human cells exhibit E1B 19K-dependent repression of virally induced, NF-κB-dependent macrophage cytokine responses (J. R. Radke, F. Grigera, D. S. Ucker, and J. L. Cook, J Virol 88:2658-2669, 2014, http://dx.doi.org/10.1128/JVI.02372-13). The more virulent, emergent strain of Ad14, Ad14p1, causes increased cytopathology in vitro, which suggested a possible E1B 20K defect. Whether there is a linkage between these observations was unknown. We show that there is markedly reduced expression of E1B 20K in Ad14p1-infected human cells and that this causes an increased proinflammatory cytokine response of human alveolar macrophages and more severe inflammatory lung disease in infected hamsters. This is the first evidence of a clinical relevance of differential expression of the small Ad E1B gene product. The results suggest that there is a low, critical threshold of E1B 19/20K expression that is needed for viral replication and infection transmission but that a higher level of E1B 19/20K expression is required for the usual repression and control of the Ad-triggered host innate immune response.

Granulomatous hepatitis due to Bartonella henselae infection in an immunocompetent patient.

BACKGROUND: Bartonella henselae (B. henselae) is considered a rare cause of granulomatous hepatitis. Due to the fastidious growth characteristics of the bacteria, the limited sensitivity of histopathological stains, and the non-specific histological findings on liver biopsy, the diagnosis of hepatic bartonellosis can be difficult to establish. Furthermore, the optimal treatment of established hepatic bartonellosis remains controversial. CASE PRESENTATION: We present a case of hepatic bartonellosis in an immunocompetent woman who presented with right upper quadrant pain and a five cm right hepatic lobe mass on CT scan. The patient underwent a right hepatic lobectomy. Surgical pathology revealed florid necrotizing granulomatous hepatitis, favoring an infectious etiology. Despite extensive histological and serological evaluation a definitive diagnosis was not established initially. Thirteen months after initial presentation, hepatic bartonellosis was diagnosed by PCR studies from surgically excised liver tissue. Interestingly, the hepatic granulomas persisted and Bartonella henselae was isolated from the patient's enriched blood culture after several courses of antibiotic therapy. CONCLUSION: The diagnosis of hepatic bartonellosis is exceedingly difficult to establish and requires a high degree of clinical suspicion. Recently developed, PCR-based approaches may be required in select patients to make the diagnosis. The optimal antimicrobial therapy for hepatic bartonellosis has not been established, and close follow-up is needed to ensure successful eradication of the infection.

An unusual association between hemophagocytic lymphohistiocytosis, mixed connective tissue disease, and autoimmune hemolytic anemia: A case report.

RATIONALE: In the adult patient, hemophagocytic lymphohistiocytosis (HLH) is uncommon and frequently difficult to diagnose due to its nonspecific presentation and numerous complications. PATIENT CONCERNS: Herein, we present the case of a 25-year-old female who initially presented for evaluation of persistent fevers and fatigue. She was found to have splenomegaly, generalized lymphadenopathy, pancytopenia, and acute hepatic failure. DIAGNOSES, INTERVENTIONS, AND OUTCOMES: Her course was further complicated by the development of nephrotic syndrome and autoimmune hemolytic anemia (AIHA). Antinuclear antibody and ribonucleoprotein were positive, with concurrent physical examination findings, indicating underlying mixed connective tissue disease (MCTD). Ferritin was greater than 40,000 ng/dL. Viral studies, including hepatitis A, B, and C, cytomegalovirus, and Epstein-Barr virus were negative. On the basis of her clinical presentation, a diagnosis of HLH secondary to MCTD was made. This was later confirmed on liver biopsy. She was started on high-dose prednisone and her symptoms completely resolved. She was then transitioned to azathioprine, hydroxychloroquine, prophylactic antibiotics, and a prednisone taper for long-term management. LESSONS: This case is notable for the association of both AIHA and MCTD with HLH, providing support for a possible relationship between these 3 conditions.

Endotoxin potentiates hepatocyte apoptosis in cholestasis.

BACKGROUND: Cholestasis is a component of liver disease of almost any etiology, including septic liver injury. The cellular mechanisms of liver injury in cholestasis and sepsis remain unresolved. We evaluated apoptosis, a well-orchestrated and potentially reversible mechanism of cell death, in bile duct-ligated and endotoxin-injected rats. STUDY DESIGN: Male Sprague-Dawley rats were randomly assigned to six groups (n = 6-9): bile duct-ligated+endotoxin (B+E), sham+endotoxin (S+E), bile duct-ligated (B), sham (S), endotoxin (E), and normal (N). On day 1, the bile ducts of B+E and B rats were ligated and severed. S+E and S animals underwent biliary manipulation only. On day 3, B+E, S+E, and E groups received 3 mg/kg endotoxin i.v.. On day 4, livers from all rats were excised, fixed, and stained (hematoxylin and eosin and terminal deoxynucleotidyl transferase dUTP nick-end labeling [TUNEL]). Portions were frozen for DNA fragmentation analysis. Caspase 3 activity was determined using isolated hepatocytes. RESULTS: Livers from all groups (B+E, S+E, E, and B) except normal and sham displayed apoptosis by hematoxylin and eosin staining, TUNEL staining, and DNA fragmentation. Histologic evaluation revealed 10% to 20% necrosis in endotoxin-treated animals (B+E, S+E, and E). Caspase 3 activity was significantly higher in endotoxin-treated animals versus animals without endotoxin (treated 0.450 +/- 0.08 versus nontreated 0.135 +/- 0.05, p < 0.0001) (mean +/- SD). CONCLUSIONS: Cholestatic livers had apoptosis without progression to necrosis. When exposed to the second insult of endotoxin, cholestatic livers received an acute on chronic apoptotic trigger, and proceeded to necrosis. Endotoxin was a potent hepatotoxic insult because all treated rat livers displayed both apoptosis and necrosis.

Malakoplakia of liver diagnosed by a needle core biopsy: a case report and review of the literature.

Although malakoplakia of the genitourinary tract and colon is reported frequently in the literature, malakoplakia that occurs primarily in the liver is rare, and only 4 cases have been described thus far. To our knowledge, this is the first case of malakoplakia of the liver diagnosed by a needle core biopsy. This case occurred in a 19-year-old man with small bowel ileus following Klebsiella pneumonia.