The Secretome of Adult Murine Hookworms Is Shaped by Host Expression of STAT6.

Co-evolutionary adaptation of hookworms with their mammalian hosts has been selected for immunoregulatory excretory/secretory (E/S) products. However, it is not known whether, or if so, how host immunological status impacts the secreted profile of hematophagous adult worms. This study interrogated the impact of host Signal transducer and activator of transcription 6 (STAT6) expression during the experimental evolution of hookworms through the sequential passage of the life cycle in either STAT6 deficient or WT C57BL/6 mice. Proteomic analysis of E/S products by LC-MS showed increased abundance of 15 proteins, including myosin-3, related to muscle function, and aconitate hydratase, related to iron homeostasis. However, most E/S proteins (174 of 337 unique identities) were decreased, including those in the Ancylostoma-secreted protein (ASP) category, and metallopeptidases. Several identified proteins are established immune-modulators such as fatty acid-binding protein homologue, cystatin, and acetylcholinesterase. Enrichment analysis of InterPro functional categories showed down-regulation of Cysteine-rich secretory proteins, Antigen 5, and Pathogenesis-related 1 proteins (CAP), Astacin-like metallopeptidase, Glycoside hydrolase, and Transthyretin-like protein groups in STAT6 KO-adapted worms. Taken together, these data indicate that in an environment lacking Type 2 immunity, hookworms alter their secretome by reducing immune evasion proteins- and increasing locomotor- and feeding-associated proteins.

"Every cell is an immune cell; contributions of non-hematopoietic cells to anti-helminth immunity".

Helminths are remarkably successful parasites that can invade various mammalian hosts and establish chronic infections that can go unnoticed for years despite causing severe tissue damage. To complete their life cycles, helminths migrate through multiple barrier sites that are densely populated by a complex array of hematopoietic and non-hematopoietic cells. While it is clear that type 2 cytokine responses elicited by immune cells promote worm clearance and tissue healing, the actions of non-hematopoietic cells are increasingly recognized as initiators, effectors and regulators of anti-helminth immunity. This review will highlight the collective actions of specialized epithelial cells, stromal niches, stem, muscle and neuroendocrine cells as well as peripheral neurons in the detection and elimination of helminths at mucosal sites. Studies dissecting the interactions between immune and non-hematopoietic cells will truly provide a better understanding of the mechanisms that ensure homeostasis in the context of helminth infections.

Trefoil Factor Family: A Troika for Lung Repair and Regeneration.

Tissue damage in the upper and lower airways caused by mechanical abrasion, noxious chemicals, or pathogenic organisms must be followed by rapid restorative processes; otherwise, persistent immunopathology and disease may ensue. This review will discuss evidence for the important role served by trefoil factor (TFF) family members in healthy and diseased airways of humans and rodents. Collectively, these peptides serve to both maintain and restore homeostasis through their regulation of the mucous layer and their control of cell motility, cell differentiation, and immune function in the upper and lower airways. We will also discuss important differences in which trefoil member tracks with homeostasis and disease between humans and mice, which poses a challenge for research in this area. Moreover, we discuss new evidence supporting newly identified receptor binding partners in the leucine-rich repeat and immunoglobulin-like domain-containing NoGo (LINGO) family in mediating the biological effects of TFF proteins in mouse models of epithelial repair and infection. Recent advances in our knowledge regarding TFF peptides suggest that they may be reasonable therapeutic targets in the treatment of upper and lower airway diseases of diverse etiologies. Further work understanding their role in airway homeostasis, repair, and inflammation will benefit from these newly uncovered receptor-ligand interactions.

Parasitic helminth infections in humans modulate Trefoil Factor levels in a manner dependent on the species of parasite and age of the host.

Helminth infections, including hookworms and Schistosomes, can cause severe disability and death. Infection management and control would benefit from identification of biomarkers for early detection and prognosis. While animal models suggest that Trefoil Factor Family proteins (TFF2 and TFF3) and interleukin-33 (IL-33) -driven type 2 immune responses are critical mediators of tissue repair and worm clearance in the context of hookworm infection, very little is known about how they are modulated in the context of human helminth infection. We measured TFF2, TFF3, and IL-33 levels in serum from patients in Brazil infected with Hookworm and/or Schistosomes, and compared them to endemic and non-endemic controls. TFF2 was specifically elevated by Hookworm infection in females, not Schistosoma or co-infection. This elevation was correlated with age, but not worm burden. TFF3 was elevated by Schistosoma infection and found to be generally higher in females. IL-33 was not significantly altered by infection. To determine if this might apply more broadly to other species or regions, we measured TFFs and cytokine levels (IFNγ, TNFα, IL-33, IL-13, IL-1ß, IL-17A, IL-22, and IL-10) in both the serum and urine of Nigerian school children infected with S. haematobium. We found that serum levels of TFF2 and 3 were reduced by infection, likely in an age dependent manner. In the serum, only IL-10 and IL-13 were significantly increased, while in urine IFN-γ, TNF-α, IL-13, IL-1ß, IL-22, and IL-10 were significantly increased in by infection. Taken together, these data support a role for TFF proteins in human helminth infection.

Photophobia in primary headaches.

BACKGROUND: Photophobia is a debilitating feature of many headache disorders. OVERVIEW: Clinical and preclinical research has identified several potential pathways involved in enhanced light sensitivity. Some of these structures include trigeminal afferents in the eye, second-order neurons in the trigeminal nucleus caudalis, third-order neurons in the posterior thalamus, modulatory neurons in the hypothalamus, and fourth-order neurons in the visual and somatosensory cortices. It is unclear to what degree each site plays a role in establishing the different temporal patterns of photophobia across different disorders. Peptides such as calcitonin gene-related peptide and pituitary adenylate cyclase-activating polypeptide may play a role in photophobia at multiple levels of the visual and trigeminal pathways. CONCLUSION: While our understanding of photophobia has greatly improved in the last decade, there are still unanswered questions. These answers will help us develop new therapies to provide relief to patients with primary headache disorders.

Anal complications after restorative proctocolectomy (J-pouch).

A prospective assessment was performed to determine the incidence of anal complications after ileoanal J-pouch anastomosis procedures for ulcerative colitis (UC) and familial adenomatous polyposis (FAP). From 1989 to 2000, 75 patients (50 male and 25 female) underwent proctocolectomy and ileal pouch-anal anastomosis with temporary loop ileostomy for UC (N = 68) and FAP (N = 7). Overall 33 patients (44%) developed anal complications postoperatively. Nineteen patients (25%) had mild anal stenosis amenable to digital dilatation in the office. Ten patients (13%) had severe anal stenosis requiring operative dilatation. Ileostomy closure was delayed longer than 3 months in four patients because of anal stenosis. One patient never had his ileostomy closed secondary to severe anal stenosis. Anal fissures developed in one patient that resolved with conservative treatment. Three patients developed fistula-in-ano and one patient developed a pouch-vaginal fistula. Of these four patients two later manifested signs of Crohn's disease. Four patients developed perirectal abscesses (three without fistulas) that were treated with incision and drainage. Two patients had presacral (anastomotic) abscesses; one patient was treated with temporary anastomotic diversion and the other underwent a permanent ileostomy and pouch resection. Both of these patients were later diagnosed with Crohn's disease. Anal complications developed in 17 of 41 (41%) handsewn anastomoses, 16 of 34 (47%) stapled anastomoses, three of seven (43%) patients with FAP, and 30 of 68 (44%) patients with UC. Operative technique and disease type did not significantly correlate with the type of anal complication. However, hand-sewn anastomoses had a higher incidence of severe strictures and FAP patients did not develop anal abscesses, fistulas, or fissures. Forty-five per cent of our patients with abscesses/fistulas and all of our patients with presacral abscesses from anastomotic dehiscence were later diagnosed with Crohn's disease. Anal complications after ileoanal J-pouch anastomosis are relatively common.