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Atg16l1 Deficiency Confers Protection from Uropathogenic Escherichia Coli

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Atg16l1 Deficiency Confers Protection from Uropathogenic Escherichia Coli Atg16L1 deficiency confers protection from uropathogenic Escherichia coli infection in vivo Caihong Wanga,1, Graziella R. Mendonsaa,1, Jane W. Symingtona,1, Qunyuan Zhangb, Ken Cadwellc,2, Herbert W. Virginc,d, and Indira U. Mysorekara,c,3 Departments of aObstetrics and Gynecology, bGenetics, and cPathology and Immunology, and dMidwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research, Washington University School of Medicine, St. Louis, MO 63110 Edited* by Roy Curtiss III, Arizona State University, Tempe, AZ, and approved May 22, 2012 (received for review March 7, 2012) Urinary tract infection (UTI), a frequent and important disease in the microtubule-associated protein light chain 3 (LC3) to autopha- humans, is primarily caused by uropathogenic Escherichia coli (UPEC). gosomes en route to their fusion with lysosomes (1, 10). We pre- HM UPEC forms acute cytoplasmic biofilms within superficial urothelial viously showed that mice deficient in Atg16L1 (Atg16L1 )display cells and can persist by establishing membrane-enclosed latent reser- reduced autophagy. In addition, they develop, on viral infection, ’ voirs to seed recurrent UTI. The host responds with an influx of innate intestinal abnormalities similar to pathologies found in Crohn s immune cells and shedding of infected epithelial cells. The autophagy disease patients, including abnormalities in the integrity, architec- gene ATG16L1 has a commonly occurring mutation that is associated ture, and function of Paneth cells, which are specialized secretory with inflammatory disease and intestinal cell abnormalities in mice epithelial cells of the small intestine (11, 12). Atg16L1 has also been HM shown to play a role in modulating proinflammatory responses and humans. Here, we show that Atg16L1-deficient mice (Atg16L1 ) in mice and humans (13, 14). Furthermore, population genetic cleared bacteriuria more rapidly and thoroughly than controls and studies have positively associated a common polymorphism in the showed rapid epithelial recovery. Atg16L1 deficiency was associated fl fl ATG16L1 gene with in ammatory bowel disease (15, 16). One ex- with a potent proin ammatory cytokine response with increased re- planation for a high prevalence of such harmful gene variants would cruitment of monocytes and neutrophils to infected bladders. Chime- HM be protection from common infections. However, such a protective ric and genetic studies showed that Atg16L1 hematopoietic cells role for mutation of an autophagy gene has not been reported. alone could increase clearance and that Atg16L1-deficient innate im- Here, we use Atg16L1HM mice as a genetically tractable model to mune cells were required and sufficient for enhanced bacteriuric determine whether mutation in an autophagy gene can increase clearance. We also show that Atg16L1-deficient mice exhibit cell-au- resistance to a common infection. Urinary tract infections (UTIs), tonomous architectural aberrations of superficial urothelial cells, in- primarily caused by uropathogenic Escherichia coli (UPEC), are cluding increases in multivesicular bodies, lysosomes, and expression among the most common infectious diseases in humans, resulting in of the UPEC receptor Up1a. Finally, we show that Atg16L1HM epithe- an estimated 13 million outpatient visits yearly in the United States lial cells contained a significantly reduced number of latent reservoirs. (17). Recurrent UTIs are a serious problem, with ∼25% of patients Together, our results show that Atg16L1 deficiency confers protec- experiencing multiple episodes per year despite appropriate anti- tion in vivo to the host against both acute and latent UPEC infection, biotic treatment and absence of bacteriuria between episodes (18). suggestthatdeficiency in a key autophagy protein can be protective In an in vivo mouse model, UPEC invades bladder superficial cells against infection in an animal model of one of the most common by binding uroplakin receptors expressed on the cell surface (19, fi 20). During the acute stage of infection (0–72 h), intracellular diseases of women worldwide, and may have signi cant clinical fi implications for understanding the etiology of recurrent UTIs. UPEC replicates rapidly and establishes cytoplasmic bio lms termed intracellular bacterial communities (IBCs) in bladders of both mice and humans (21, 22). Major mechanisms for control of Atg5 | Lyz-Cre | Rag1 UPEC-induced UTI include exfoliation of the superficial epithelial cell layer containing IBCs into the urine and influx of innate im- acroautophagy (henceforth, autophagy) is a well-conserved mune cells (23–26). However, despite the innate immune host re- Mcellular pathway required to maintain cellular homeostasis, sponse, a subset of UPEC still survives and establishes long-term recycle cellular components, and eliminate intracellular pathogens reservoirs within urothelial cells, termed quiescent intracellular (1, 2). In response to nutrient deprivation, stress, or other signals, reservoirs (QIRs) (27), which are enclosed within vesicles deco- double membrane-bound autophagosomes are recruited to envelop rated with late endosomal/lysosomal markers. Latent UPEC within bulk cytoplasm, damaged organelles, large cytoplasmic protein QIRs can reemerge to seed recurrent UTIs likely through cAMP- aggregates, or invading pathogens. These autophagosomes then regulated exocytic processes to reenter the bladder lumen con- fuse with lysosomes, and therefore, their cargo may be degraded. comitant with urothelial regeneration (27–29). Autophagy genes and proteins play a multiplicity of roles in both innate and adaptive immunity (3–5). For example, in mice deficient Results for Atg5 in macrophages and neutrophils, there is increased sus- Atg16L1 Deficiency Leads to Superficial Cell Architectural Abnormalities. ceptibility to infection with Listeria monocytogenes and Toxoplasma To determine if Atg16L1 plays a role in UPEC invasion and gondii, and Atg5 deficiency is associated with decreased resistance persistence within the bladder, we first examined the morphology to viral encephalitis (6, 7). Pathogens have also evolved sophisti- cated mechanisms to evade or subvert the host autophagy ma- chinery for survival and persistence within cells (8) by blocking the Author contributions: C.W., G.R.M., J.W.S., and I.U.M. designed research; C.W., G.R.M., xenophagic degradation of intracellular pathogens or the function and J.W.S. performed research; C.W., G.R.M., J.W.S., and Q.Z. analyzed data; and C.W., of autophagy in innate and adaptive immunity. Although most work G.R.M., J.W.S., K.C., H.W.V., and I.U.M. wrote the paper. to date shows that autophagy as a whole and specificautophagy The authors declare no conflict of interest. proteins are detrimental to the microorganism, they may also have *This Direct Submission article had a prearranged editor. proviral or probacterial effects. For example, autophagosomes may 1C.W., G.R.M., and J.W.S. contributed equally to this work. serve as a protected niche for intracellular bacteria and/or source of 2Present address: Skirball Institute of Biomolecular Medicine, Department of Microbiol- nutrients for intracellular pathogens (9). In vivo evidence of such ogy, New York University School of Medicine, New York, NY 10016. a propathogen role of autophagy is still lacking. 3To whom correspondence should be addressed. E-mail: [email protected]. The autophagy gene/protein Atg16L1 plays a key role in auto- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. phagosome maturation as part of a protein complex that directs 1073/pnas.1203952109/-/DCSupplemental. 11008–11013 | PNAS | July 3, 2012 | vol. 109 | no. 27 www.pnas.org/cgi/doi/10.1073/pnas.1203952109 Downloaded by guest on September 29, 2021 of superficial urothelial cells, the target cells for UPEC invasion, in WT HM Atg16L1HM mice. These cells are highly specialized to rapidly ex- A DIC B DIC pand and shrink as the bladder fills and contracts, and this function E-cad E-cad requires large plaques of hexagonal arrays of uroplakin protein complexes, which are transported by discoidal fusiform vesicles (FVs) and multivesicular bodies (MVBs) to maintain cellular ar- chitecture and barrier properties (30, 31). UPEC uses the uropla- kins (Up1a) as receptors to facilitate invasion and entry into these urothelial cells (30–32). We reasoned that Atg16L1 deficiency might alter this membranous intracellular network, because changes C D in intracellular membranes associated with granule exocytosis are observed in the intestinal Paneth cell in Atg16L1HM mice (11). Here, we show that Atg16L1 deficiency governs urothelial cell ar- chitecture as follows. First, bladders of Atg16L1HM mice exhibited decreased (by 78%) Atg16L1 expression (Fig. S1). Second, super- ficial epithelial cells of uninfected Atg16L1HM mice showed dra- matic accumulation of vesicles (Fig. 1B) compared with those cells of control (WT) mice (Fig. 1A). Transmission EM (TEM) con- E F firmed this vesicular congestion (Fig. 1 C–F and Fig. S2 A–C)and revealed significantly greater numbers of organelles with the mor- phology of MVBs and lysosomes in Atg16L1HM superficial cells (Fig. 1 G and H)(P < 0.05 and P < 0.01,respectively).Third,given that this vesicular system is responsible for uroplakin transport and recycling and that disruption in vesicular trafficking of FVs and MVBs is associated with aberrant MVB accumulation (28, 30, 33), we next determined the effect of Atg16L1 deficiency on uroplakin WT WT G H 2 receptor expression. We found increased Up1a
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