<i>Mycobacterium avium paratuberculosis</i>Invades Human Small‐Intestinal Goblet Cells and Elicits Inflammation

Golan, L.; Livneh-Kol, Ayala; Gonen, Erez; Yagel, Simcha; Rosenshine, Ilan; Shpigel, Nahum Y.

doi:10.1086/596033

Cited by 39 publications

(47 citation statements)

References 15 publications

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“…MICs of the dihydrophthalazines for pneumococci, group A streptococci, and M. catarrhalis were far lower than those of Tmp and comparable to those of Lvx. The dihydrophthalazines also showed very interesting activities against M. avium, an established pulmonary pathogen (30,38) which has been implicated in inflammatory bowel diseases (22,29) and which is the subject of considerable effort vis-à-vis antifolate therapy (1,21). However, BAL0030543, BAL0030544, and BAL0030545 showed relatively poor in vitro activities toward H. influenzae.…”

Section: Discussionmentioning

confidence: 99%

In Vitro and In Vivo Properties of Dihydrophthalazine Antifolates, a Novel Family of Antibacterial Drugs

Caspers

Bury

Gaucher

et al. 2009

Antimicrob Agents Chemother

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Racemic 2,4-diaminopyrimidine dihydrophthalazine derivatives BAL0030543, BAL0030544, and BAL0030545 exhibited low in vitro MICs toward small, selected panels of Enterococcus faecalis, Enterococcus faecium, Streptococcus pneumoniae, Moraxella catarrhalis, and Mycobacterium avium, though the compounds were less active against Haemophilus influenzae. The constellation of dihydrofolate reductases (DHFRs) present in 20 enterococci and 40 staphylococci was analyzed and correlated with the antibacterial activities of the dihydrophthalazines and trimethoprim. DHFRs encoded by dfrB, dfrA (S1 isozyme), dfrE, and folA were susceptible to the dihydrophthalazines, whereas DHFRs encoded by dfrG (S3 isozyme) and dfrF were not. Studies with the separated enantiomers of BAL0030543, BAL0030544, and BAL0030545 revealed preferential inhibition of susceptible DHFRs by the (R)-enantiomers. BAL0030543, BAL0030544, and BAL0030545 were well tolerated by mice during 5-and 10-day oral toxicity studies at doses of up to 400 mg/kg of body weight. Using a nonoptimized formulation, the dihydrophthalazines displayed acceptable oral bioavailabilities in mice, and efficacy studies with a septicemia model of mice infected with trimethoprim-resistant, methicillin-resistant Staphylococcus aureus gave 50% effective dose values in the range of 1.6 to 6.25 mg/kg.Despite sustained efforts to identify new drugs against antibiotic-resistant bacteria, treatment of infections caused by vancomycin-resistant enterococci and methicillin-resistant staphylococci continues to challenge clinicians (5). Enterococci are often associated with urinary tract infections, intra-abdominal abscesses, endocarditis, and bacteremia, whereas staphylococci are common causes of skin and skin structure infections, endocarditis, osteomyelitis, prosthetic joint infections, catheterrelated bacteremia, and nosocomial pneumonia. Methicillinresistant Staphylococcus aureus (MRSA) accounts for approximately 50% of all S. aureus infections in the United States (24). Once confined to healthcare settings, MRSA has emerged as a serious cause of community-acquired skin and skin structure infections (32), and an increased frequency of skin cultures positive for S. aureus is associated with nasal and intestinal colonization (2).Dihydrofolate reductase (DHFR; EC 1.5.1.3) is an essential enzyme in most pathogenic bacteria, and the clinical success of trimethoprim (28,33,41,43) confirms DHFR as an important chemotherapeutic target. A phenylalanine3tyrosine substitution at position 98 in the wild-type, nontransferable, chromosomally encoded DHFR renders S. aureus resistant to trimethoprim (15); a corresponding tyrosyl residue occurs in transferable plasmid-encoded wild-type staphylococcal DHFR isozymes S1, S2, and S3 (13,14,40) and in the enterococcal DHFRs encoded by dfrE and dfrF. The gene encoding DHFR S1 may also be associated with staphylococcal chromosomal cassette mec N1 (SCCmec-N1) (37).BAL0030543, BAL0030544, and BAL0030545 are novel dihydrophthalazine antifolates with potent activities a...

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Section: Discussionmentioning

confidence: 99%

In Vitro and In Vivo Properties of Dihydrophthalazine Antifolates, a Novel Family of Antibacterial Drugs

Caspers

Bury

Gaucher

et al. 2009

Antimicrob Agents Chemother

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“…Our model was found to be highly reproducible and specific in its ability to recapitulate natural infections by enteric pathogens like enterohemorrhagic E. coli (EHEC) O157:H7 (21) and the probable zoonotic pathogen Mycobacterium avium subsp. paratuberculosis (22). In the current study, we expanded our validation to EPEC.…”

Section: Enteropathogenic E Coli Infection In the Human Gutmentioning

confidence: 99%

Type Three Secretion System-Dependent Microvascular Thrombosis and Ischemic Enteritis in Human Gut Xenografts Infected with Enteropathogenic Escherichia coli

et al. 2017

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Enteropathogenic Escherichia coli (EPEC) is a leading cause of severe intestinal disease and infant mortality in developing countries. Virulence is mediated by a type three secretion system (T3SS), causing the hallmark attaching and effacing (AE) lesions and actin-rich pedestal formation beneath the infecting bacteria on the apical surface of enterocytes. EPEC is a human-specific pathogen whose pathogenesis cannot be studied in animal models. We therefore established an EPEC infection model in human gut xenografts in SCID mice and used it to study the role of T3SS in the pathogenesis of the disease. Following EPEC O127:H6 strain E2348/69 infection, T3SS-dependent AE lesions and pedestals were demonstrated in all infected xenografts. We report here the development of T3SS-dependent intestinal thrombotic microangiopathy (iTMA) and ischemic enteritis in ϳ50% of infected human gut xenografts. Using species-specific CD31 immunostaining, we showed that iTMA was limited to the larger human-mouse chimeric blood vessels, which are located between the muscularis mucosa and circular muscular layer of the human gut. These blood vessels were massively invaded by bacteria, which adhered to and formed pedestals on endothelial cells and aggregated with mouse neutrophils in the lumen. We conclude that endothelial infection, iTMA, and ischemic enteritis might be central mechanisms underlying severe EPEC-mediated disease.

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“…In addition, mucussecreting goblet cells of the small intestine and goat enterocytes have been involved in M. avium subsp. paratuberculosis uptake (7,17). This choice of cell type for entry likely contributes to the ability of M. avium subsp.…”

Section: The Process Of Invasionmentioning

confidence: 99%

“…This M. avium subsp. paratuberculosis internalizationdependent tissue activation is also accompanied by inflammation from infiltrating neutrophils and macrophages at the site of invasion (7,10,22). Of note is that when calves are infected, no inflammatory manifestation of clinical relevance takes place.…”

Section: Avium Subsp Paratuberculosis Affects the Integrity Of Thmentioning

confidence: 99%

“…The disease course generally takes 2 to 5 years before clinical signs appear. Two hallmarks of advanced disease are the thick, inflexible intestinal sections observed from the strikingly inflamed epithelial cell layer (6,7) and granuloma formation in the small intestine and regional lymph nodes (8). This is due to the massive influx of proinflammatory cells at the site of infection.…”

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No Holes Barred: Invasion of the Intestinal Mucosa by Mycobacterium avium subsp. paratuberculosis

Bannantine

Bermudez

2013

Infect Immun

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The infection biology of Mycobacterium avium subsp. paratuberculosis has recently crystallized, with added details surrounding intestinal invasion. The involvement of pathogen-derived effector proteins such as the major membrane protein, oxidoreductase, and fibronectin attachment proteins have been uncovered. Mutations constructed in this pathogen have also shed light on genes needed for invasion. The host cell types that are susceptible to invasion have been defined, along with their transcriptional response. Recent details have given a new appreciation for the dynamic interplay between the host and bacterium that occurs at the outset of infection. An initial look at the global expression pathways of the host has shown a circumvention of the cell communication pathway by M. avium subsp. paratuberculosis, which loosens the integrity of the tight junctions. We now know that M. avium subsp. paratuberculosis activates the epithelial layer and also actively recruits macrophages to the site of infection. These notable findings are summarized along with added mechanistic details of the early infection model. We conclude by proposing critical next steps to further elucidate the process of M. avium subsp. paratuberculosis invasion.

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Mycobacterium avium paratuberculosisInvades Human Small‐Intestinal Goblet Cells and Elicits Inflammation

Cited by 39 publications

References 15 publications

In Vitro and In Vivo Properties of Dihydrophthalazine Antifolates, a Novel Family of Antibacterial Drugs

In Vitro and In Vivo Properties of Dihydrophthalazine Antifolates, a Novel Family of Antibacterial Drugs

Type Three Secretion System-Dependent Microvascular Thrombosis and Ischemic Enteritis in Human Gut Xenografts Infected with Enteropathogenic Escherichia coli

No Holes Barred: Invasion of the Intestinal Mucosa by Mycobacterium avium subsp. paratuberculosis

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