MyD88 Restricts F. tularensis Pathogenesis
Inhalation of Francisella tularensis results in pneumonic tularemia, an infection associated with high mortality rates. Using mice deficient in myeloid differentiation primary response gene 88 (MyD88), a key innate immunity signaling molecule, Russo et al (Am J Pathol 2013, 183:1223–1232) investigated the pathological consequences of the innate immune response following F. tularensis infection. MyD88 knockout mice succumbed to infection faster than wild-type mice due to greater bacterial burdens in lungs and distal organs as well as the absence of IFN-γ in the lungs, spleens, and sera. Despite the absence of cellular infiltration, cell death in the lungs of MyD88 knockout mice was higher than in wild-type mice. These results highlight a previously unappreciated role for the host response during infection with virulent F. tularensis.
HSV-1 Targets Lymphatic Vessels in CD118−/− Mice
Herpes simplex virus type-1 (HSV-1) induces lymphangiogenesis in the infected cornea. Bryant-Hudson et al (Am J Pathol 2013, 183:1233–1242) examined the impact of HSV-1 replication on lymphangiogenesis and angiogenesis using immunocompetent type I interferon (IFN) receptor-deficient (CD118−/−) mice. Impairment of type I IFN signaling resulted in transient lymphatic vessel growth, stable blood vessel growth, extensive corneal edema, and loss of epithelial layers due to robust viral replication and skewed leukocyte recruitment. HSV-1 selectively targeted lymphatic vessels, but not blood vessels, during acute infection, underscoring the key role of the type I IFN pathway in maintaining corneal structural integrity in addition to its antiviral role.
Revisiting the Pandemic H1N1 Virus of 2009
Fatal cases of 2009 pandemic influenza H1N1 virus (2009 pH1N1) infection differ from seasonal influenza virus infections, and the host immune response to 2009 pH1N1 is poorly understood. Gao et al (Am J Pathol 2013, 183:1258–1268) analyzed autopsied lung tissues from fatal 2009 pH1N1 cases. Pathogenesis of the viral infection was associated with both viral replication and production of proinflammatory mediators. In addition, FasL and caspase-3 were involved in the apoptotic process frequently observed in lung and airway tissues of 2009 pH1N1 fatal cases. The disequilibrium between Fas and FasL levels in the lung may contribute to delayed clearance of virus and subsequent pathological damage, having implications on clinical treatment strategies.
Mesangial Invasion of Alport Glomerular Capillaries
Alport syndrome results from mutations in type IV collagen genes, but the mechanism for delayed glomerular disease onset is unknown. Zallocchi et al (Am J Pathol 2013, 183:1269–1280) examined two mouse models and human kidney tissue to explore disease progression. Laminin accumulated in the glomerular basement membrane (GBM) in the mice. Mesangial processes invading the capillary loops of both mouse models, as well as in human Alport glomeruli, were the likely source of this laminin. Mesangial cell process invasion was enhanced by l-NAME salt-induced hypertension in vivo, reduced by treatment with Rac1 inhibitor or deletion of integrin α1 in vitro, and ameliorated on laminin deletion in Alport mice. These data define a role for biomechanical strain-mediated induction of mesangial cell process invasion as a key aspect of Alport glomerular disease initiation, setting the stage for novel therapeutic targets aimed at blocking this process.
OLFM4 Suppresses Prostate Cancer Progression
The olfactomedin 4 (OLFM4) gene is located on chromosome 13q14.3, which is frequently deleted in prostate cancer. Using various molecular techniques, Li et al (Am J Pathol 2013, 183:1329–1338) investigated the genetics, protein expression, and functions of OLFM4 in prostate cancer. Patient sample and tissue array data correlated OLFM4 deletion with prostate cancer, whereas tissue array and in vitro data inversely correlated OLFM4 protein expression with advanced prostate cancer. OLFM4 may play an important tumor suppressor role in the progression of prostate cancer and may serve as a molecular target for improving prostate cancer prognostic and therapeutic approaches.
Published online: August 28, 2013
© 2013 American Society for Investigative Pathology. Published by Elsevier Inc.
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- HSV-1 Targets Lymphatic Vessels in the Eye and Draining Lymph Node of Mice Leading to Edema in the Absence of a Functional Type I Interferon ResponseThe American Journal of PathologyVol. 183Issue 4
- PreviewHerpes simplex virus type-1 (HSV-1) induces new lymphatic vessel growth (lymphangiogenesis) in the cornea via expression of vascular endothelial growth factor by virally infected epithelial cells. Here, we extend this observation to demonstrate the selective targeting of corneal lymphatics by HSV-1 in the absence of functional type I interferon (IFN) pathway. Specifically, we examined the impact of HSV-1 replication on angiogenesis using type I IFN receptor deficient (CD118−/−) mice. HSV-1-induced lymphatic and blood vessel growth into the cornea proper was time-dependent in immunocompetent animals.
- α1β1 Integrin/Rac1-Dependent Mesangial Invasion of Glomerular Capillaries in Alport SyndromeThe American Journal of PathologyVol. 183Issue 4
- PreviewAlport syndrome, hereditary glomerulonephritis with hearing loss, results from mutations in type IV collagen COL4A3, COL4A4, or COL4A5 genes. The mechanism for delayed glomerular disease onset is unknown. Comparative analysis of Alport mice and CD151 knockout mice revealed progressive accumulation of laminin 211 in the glomerular basement membrane. We show mesangial processes invading the capillary loops of both models as well as in human Alport glomeruli, as the likely source of this laminin. l-NAME salt–induced hypertension accelerated mesangial cell process invasion.
- Deletion of the Olfactomedin 4 Gene Is Associated with Progression of Human Prostate CancerThe American Journal of PathologyVol. 183Issue 4
- PreviewThe olfactomedin 4 (OLFM4) gene is located on chromosome 13q14.3, which frequently is deleted in human prostate cancer. However, direct genetic evidence of OLFM4 gene alteration in human prostate cancer has not yet been obtained. In this study, we investigated the genetics, protein expression, and functions of the OLFM4 gene in human prostate cancer. We found overall 25% deletions within the OLFM4 gene in cancerous epithelial cells compared with adjacent normal epithelial cells that were microdissected from 31 prostate cancer specimens using laser-capture microdissection and genomic DNA sequencing.
- Cytokine and Chemokine Profiles in Lung Tissues from Fatal Cases of 2009 Pandemic Influenza A (H1N1): Role of the Host Immune Response in PathogenesisThe American Journal of PathologyVol. 183Issue 4
- PreviewPathological studies on fatal cases caused by 2009 pandemic influenza H1N1 virus (2009 pH1N1) reported extensive diffuse alveolar damage and virus infection predominantly in the lung parenchyma. However, the host immune response after severe 2009 pH1N1 infection is poorly understood. Herein, we investigated viral load, the immune response, and apoptosis in lung tissues from 50 fatal cases with 2009 pH1N1 virus infection. The results suggested that 7 of the 27 cytokines/chemokines showed remarkably high expression, including IL-1 receptor antagonist protein, IL-6, tumor necrosis factor-α, IL-8, monocyte chemoattractant protein-1, macrophage inflammatory protein 1-β, and interferon-inducible protein-10 in lung tissues of 2009 pH1N1 fatal cases.
- MyD88-Dependent Signaling Prolongs Survival and Reduces Bacterial Burden during Pulmonary Infection with Virulent Francisella tularensisThe American Journal of PathologyVol. 183Issue 4
- PreviewFrancisella tularensis is the causative agent of the debilitating febrile illness tularemia. The severe morbidity associated with F. tularensis infections is attributed to its ability to evade the host immune response. Innate immune activation is undetectable until more than 48 hours after infection. The ensuing inflammatory response is considered pathological, eliciting a septic-like state characterized by hypercytokinemia and cell death. To investigate potential pathological consequences of the innate immune response, mice deficient in a key innate immune signaling molecule, MyD88, were studied.