By Susha Cheriyedath, M.Sc. Jul 31 2023 Reviewed by Benedette Cuffari, M.Sc.
A recent study published in PLOS Pathogens identifies the Leptospira membrane protein L36 (MPL36) as essential for its pathogenesis and, as a result, a potential target for future diagnostics and prophylactics.
Study: MPL36, a major plasminogen (PLG) receptor in pathogenic Leptospira, has an essential role during infection. Image Credit: Kateryna Kon / Shutterstock.com Background
The human plasminogen (PLG) system provides a proteolytic substrate for pathogen invasiveness and tissue damage, thereby increasing the virulence of various bacterial species. Sequestration of PLG and activation into plasmin (PLA) is important for bacterial survival, as PLA degrades fibrin clots, extracellular matrix (ECM) molecules, and the host's innate immunological proteins to enable bacteria to spread and evade immune responses ultimately.
Leptospirosis, a life-threatening infectious disease, is a zoonotic disease that accounts for over one million infections and about 60,000 deaths each year throughout the world. In severe forms of leptospirosis, patients will often experience severe hemorrhaging and acute kidney injury.
Leptospira enter the host through injured skin or mucous membranes and subsequently travel through viscous environments to ultimately reach the bloodstream. Thereafter, Leptospira participate in cellular adhesion, which is mediated by various surface proteins that interact with ECM components.
Previous studies indicate that many Leptospira proteins act as PLG receptors, some of which include outer membrane proteins (OMPs) like endostatin-like protein A (LenA), as well as Leptospiral immunoglobulin-like proteins A (LigA), LiGB, and LipL32.
To date, there remains a lack of data on the pathogenesis of leptospirosis, which has prevented the development of sensitive diagnostic instruments and efficient prophylactic treatments. The present study reports that MPL36 binds with PLG, promotes adherence to host cells, and degrades fibrinogen by converting bound PLG to PLA. About the study
The current study utilized Leptospira interrogans serovar Manilae strain L495 and its mutant stains, including Manilae mpl36 mutant complemented strain (Δmpl36+) and Leptospira biflexa serovar Patoc strain Patoc 1. These strains were cultured in Madin-Darby canine kidney (MDCK) cells, following which their growth curves were analyzed using dark-field microscopy, motility, and immunoblot assays.
Recombinant MPL36 (rMPL36) protein was produced using E. coli expression. Intrinsic tryptophan fluorescence spectroscopy and nickel affinity chromatography evaluated the tertiary structure of rMPL36, rMPL36 aa41-305, and rMPL36 aa41-235. The binding capacity of rMPL36 was determined, and the conversion of PLG bound to rMPL36 into active PLA was evaluated.
The binding of rMPL36 to ECM proteins and PLG was determined by staining for fibronectin, laminin, PLG, and bovine serum albumin (BSA). The pathogenicity of Manilae wildtype (WT) and mutant strains was also evaluated in three-week-old male Golden Syrian hamsters. Related StoriesSARS-CoV-2 spike protein's role in lung injury unraveled: promising new approach uncoveredMitochondrial repair protein discovery may lead to new anti-aging treatmentsSalk researchers uncover molecular mechanisms of HIV drug resistance
The tertiary structure of sporulation-related repeat (SPOR) domains from leptospiral species was predicted using AlphaFold and PyMOL software ClustalX to match MPL36 SPOR domain sequences from various Leptospira species. In vivo data was analyzed using Prism 9, Fisher's exact test, and analysis of variance (ANOVA) to ecludate the mechanisms of rMPL36 binding to host components and BSA. MPL36 is a crucial target for leptopsirosis
The motility assay revealed that, as compared to wild-type cells, mpl36 mutant and complemented strains did not significantly differ in their motility or growth characteristics. Immunofluorescence staining confirmed the subcellular localization of MPL36 in Leptospira as an outer membrane protein in both wild-type and complement cells.
Immunoprecipitation studies revealed that rMPL36 exhibited significant binding to both rLigA and rLigB, whereas no binding was observed between rMPL36 and fibronectin nor laminin.
However, rMPL36 was found to effectively bind to human PLG as compared to other recombinant proteins that were used as positive and negative controls. Within rMPL36, the conserved SPOR domain, which is located at the last 70 amino acids of the protein, is essential for the binding between rMPL36 and PLG.
Hamsters that were infected with the wild-type strain died between eight and nine days following infection with Leptospira. Comparatively, mpl36 mutant hamsters who were infected with 108 leptospires survived without exhibiting any symptoms of leptospirosis, thereby demonstrating the significant role of MPL36 in leptospirosis.
Convalescent sera were obtained from Brazilian individuals with laboratory-confirmed severe leptospirosis. To this end, anti-MPL36 immunoglobulin M (IgM) and IgG were observed in leptospirosis patients’ samples as compared to sera from healthy individuals. Study takeaways
MPL36 is an outer membrane Leptospira protein that is capable of binding to PLG, degrading fibrinogen, and facilitating host infection. Despite these findings, additional research is needed to better understand leptospiral pathogenesis and advance diagnostic and prevention strategies. Journal reference: Zhu, W., Passalia, F. J., Hamond, C., et al. (2023). MPL36, a major plasminogen (PLG) receptor in pathogenic Leptospira, has an essential role during infection. PLOS Pathogens. doi:10.1371/journal.ppat.1011313 https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1011313
The compressed NHL schedule for the end of the Stanley Cup playoffs, draft and free agency means that the majority of July and August is … a bit slower.
But it’s also the perfect time to refresh our Power Rankings of all 32 teams heading into 2025-26!
In addition to the latest 1-32 poll, this edition includes the top storyline for each team during the summer break.
How we rank: A panel of ESPN hockey commentators, analysts, reporters and editors sends in a 1-32 poll based on how strong each team will be in the 2025-26 season, which generates our master list.
Note: Previous ranking for each team refers to the final 2024-25 edition, published April 11. Stanley Cup odds are per ESPN BET as of July 24.
A second straight loss in the Stanley Cup Final resulted in no small amount of self-reflection — all while the proverbial sword of Damocles hangs over the franchise in Connor McDavid‘s potential free agency in 2026. One item that remains unchecked? Finding a better solution in goal.
Pre-playoff ranking: 3 Stanley Cup odds: +1000
Another trip to the Western Conference finals wasn’t enough for Peter DeBoer to save his job, who was replaced by former Stars coach Glen Gulutzan in July. How will the first full season of the Mikko Rantanen Era go?
Pre-playoff ranking: 7 Stanley Cup odds: +800
Given all the re-signings this offseason, there weren’t a bevy of high-impact free agents available. However, one of the top ones signed with the Hurricanes. How will Nikolaj Ehlers be deployed in Rod Brind’Amour’s system? And can he be the difference-maker next postseason?
Pre-playoff ranking: 4 Stanley Cup odds: +850
Same old Knights. The biggest fish in the free agency pond this offseason was Mitch Marner, and sure enough, Vegas’ front office found a way to land him. It presents a salary cap situation for the club, though that’s also nothing new. Marner visits Toronto on Jan. 23, for those in a calendar-circling mood.
Pre-playoff ranking: 1 Stanley Cup odds: +2500
The reigning Presidents’ Trophy winners as regular-season champs lost a key player in Nikolaj Ehlers this offseason, but gained perhaps the sport’s biggest X factor in Jonathan Toews, a three-time Stanley Cup winner who hasn’t played since the 2022-23 season because of health concerns.
Pre-playoff ranking: 5 Stanley Cup odds: +750
A first-round playoff loss is a bit misleading, as it was to fellow juggernaut Dallas Stars. The Avs believe they’ve solved their second-line center dilemma with a contract for 2024-25 trade addition Brock Nelson, but do they have enough depth to make another Cup run?
Pre-playoff ranking: 6 Stanley Cup odds: +2000
Toronto’s seemingly Quixotic quest to win another Stanley Cup continues. It has been an offseason of ups and downs so far. The Leafs lost Mitch Marner in a sign-and-trade with Vegas but inked one of the summer’s best deals with the new pact for Matthew Knies. As always, it’s high drama in the “centre of the hockey universe.”
Pre-playoff ranking: 2 Stanley Cup odds: +3000
Alex Ovechkin begins the 2025-26 season as the NHL’s all-time goals leader — and three away from 900. But the Caps won’t simply be feeding him pucks all season. This team will hope to get further than the second round, perhaps giving Ovi another Cup for his Hall of Fame résumé.
Pre-playoff ranking: 9 Stanley Cup odds: +1400
The Lightning continue to expertly massage their roster within the bounds of the salary cap. That continued this offseason, as they extended Yanni Gourde and Gage Goncalves for scoring depth. Another long playoff run is possible, though they’ll likely have to defeat their rivals from South Florida at some point on that road.
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Bettman shares 4 Nations tournament success with McAfee
NHL commissioner Gary Bettman joins “The Pat McAfee Show” and details the success of the 4 Nations Face-Off tournament.
Pre-playoff ranking: 8 Stanley Cup odds: +2000
After signing a bevy of veteran depth to the roster in free agency, the Kings created the NHL’s best schedule release video. It has been an exciting summer already!
Pre-playoff ranking: 13 Stanley Cup odds: +4000
At one point there was some thought that the Wild would sign Minnesota natives Brock Nelson or Brock Boeser (or both). Instead, each re-signed with his 2024-25 team. Bringing in Vladimir Tarasenko could be one of the offseason’s deftest moves, if the veteran forward can find his former scoring touch that mostly eluded him this past season.
Pre-playoff ranking: 15 Stanley Cup odds: +1600
Aside from some depth tweaks, the Devils didn’t do a ton thus far this offseason — though re-signing Jake Allen may prove to be one of the wiser roster moves. How will Luke Hughes‘ next contract impact the rest of their decisions?
Pre-playoff ranking: 12 Stanley Cup odds: +5000
After a playoff appearance this past season, it has been a relatively quiet offseason so far for St. Louis. And as of right now, the club doesn’t have the cap space to sign anyone to a bold offer sheet.
Pre-playoff ranking: 14 Stanley Cup odds: +3500
Senators GM Steve Staios has indicated that he likes what he has on the roster and expects growth from within. That was evident this offseason, as the club’s most noteworthy move was re-signing veteran forward Claude Giroux to a one-year deal.
Pre-playoff ranking: 17 Stanley Cup odds: +6000
Fresh off a somewhat surprising Stanley Cup playoff appearance, the Canadiens made one of the offseason’s boldest moves by trading two first-round picks for 25-year-old defenseman Noah Dobson, then inking him to an eight-year deal. Are the playoffs now an every-year thing for the Habs?
Pre-playoff ranking: 20 Stanley Cup odds: +3000
The Rangers switched coaches — from Cup winner Peter Laviolette to Cup winner Mike Sullivan — and found a trade destination for K’Andre Miller after the decision was made not to re-sign the restricted free agent. In between they landed one of the top available free agents, defenseman Vladislav Gavrikov. Is it enough to get them back in the postseason mix?
Pre-playoff ranking: 16 Stanley Cup odds: +15000
Another GM who believes — apparently — that growth will come from within, GM Craig Conroy told reporters that the players his front office had targeted in free agency signed elsewhere, and he didn’t feel any great need to spend $15 million-plus in cap space just to spend it. He could be onto something, as the team’s youth movement isn’t all Calder Trophy finalist Dustin Wolf — though having a great young goaltender certainly doesn’t hurt.
Pre-playoff ranking: 19 Stanley Cup odds: +4000
There was no playoff hockey in Utah this past spring, but GM Bill Armstrong pulled many different levers this offseason to put his team in the best spot to bring it there in 2026. The team traded for a potential superstar in JJ Peterka, signed proven veteran depth in Nate Schmidt and Brandon Tanev, and drafted Caleb Desnoyers with the No. 4 pick, a 200-foot center who will play a key role for the team sooner than later.
Pre-playoff ranking: 21 Stanley Cup odds: +10000
Little Caesars Arena has yet to host a playoff game. Is this the season that the drought ends? Detroit was knocking on the door this past season, and GM Steve Yzerman filled perhaps the org’s biggest need by trading for veteran goaltender John Gibson this summer.
Pre-playoff ranking: 18 Stanley Cup odds: +6000
Based on how the Canucks finished the 2024-25 season, continuity didn’t seem like the best option this summer. But aside from making a coaching change (from Rick Tocchet to Adam Foote) and trading for Evander Kane, it’s mostly status quo. That said, re-signing Brock Boeser was probably an easier option than trying to replace a player who scored 65 goals combined the past two seasons.
Pre-playoff ranking: 22 Stanley Cup odds: +10000
To the surprise of many the Blue Jackets remained in the playoff race until the final week of the season, thanks in large part to a Norris Trophy finalist campaign by Zach Werenski. The club made some depth additions this offseason — Charlie Coyle and Miles Wood will be particularly useful if they do make the 2026 playoffs. But are there some additional moves up GM Don Waddell’s sleeve before October?
Pre-playoff ranking: 23 Stanley Cup odds: +10000
New GM Mathieu Darche was not bashful in his first weeks on the job. Following the Noah Dobson trade, he and his associates drafted an A+ class, per ESPN’s Rachel Doerrie, and added an X factor forward in Jonathan Drouin. This is a team on the rise.
Pre-playoff ranking: 24 Stanley Cup odds: +10000
At some point, the Ducks’ rebuild will be over, and that day might be coming sooner than many suspect. GM Pat Verbeek was quite busy this summer, adding Chris Kreider in a trade and sending Trevor Zegras to Philly in another swap. The Ducks also added Mikael Granlund in free agency; he will be critical to their playoff chances. And if all of that wasn’t enough, they got a top-five talent in the draft class with the No. 10 pick in Roger McQueen, and then sent him to Disneyland to celebrate.
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Ducks draft pick Roger McQueen celebrates at Disneyland
Roger McQueen arrives at Disneyland to celebrate being drafted No. 10 by the Ducks.
Pre-playoff ranking: 29 Stanley Cup odds: +10000
Boston’s offseason business has primarily involved adding depth around the edges — and drafting future franchise center James Hagens, who will play another season at Boston College. Is there a big trade in store?
Pre-playoff ranking: 25 Stanley Cup odds: +20000
At some point, the longest playoff drought in the big four North American professional sports leagues will end. Will that be this season? The Sabres don’t appear better on paper than they were at the end of 2024-25, and they might even be worse, given that JJ Peterka was traded to Utah.
Pre-playoff ranking: 28 Stanley Cup odds: +7500
The Flyers began the offseason by hiring franchise legend Rick Tocchet to take over behind the bench. Then, they drafted a class of nine players who all play like him (or are built like he was in his playing days). In between, they traded for Trevor Zegras, who could wind up as the biggest steal of the offseason.
Pre-playoff ranking: 27 Stanley Cup odds: +30000
The Kraken have been patiently building a balanced roster with long-term success in mind. Can they finally turn a corner in 2025-26 after an offseason in which the big additions were Mason Marchment and Ryan Lindgren?
Pre-playoff ranking: 30 Stanley Cup odds: +10000
The Predators were the no-doubt winners of free agency in 2024 — and then missed the playoffs by a country mile in 2024-25. By contrast, the 2025 offseason included some low-key moves that should help get them back on track, including a trade for Nicolas Hague and the signings of Erik Haula and Nick Perbix.
Pre-playoff ranking: 26 Stanley Cup odds: +20000
It’s uncertain how long the trio of Sidney Crosby, Evgeni Malkin and Kris Letang will remain on the ice, and the rumors have picked up that one, two or all three could finish their NHL careers elsewhere. GM Kyle Dubas has been busy stocking the prospect cupboards, a process that will continue leading up to opening night, with Erik Karlsson and Bryan Rust frequently mentioned in trade rumors.
Pre-playoff ranking: 32 Stanley Cup odds: +50000
The Sharks are still probably a year away from a serious run at a playoff spot, but GM Mike Grier added a ton of talent to his roster this summer. No. 2 pick Michael Misa has the talent to hit the ice this season. The Sharks also signed veterans Dmitry Orlov and John Klingberg to add some experience to a defense that was lacking in that regard.
Pre-playoff ranking: 31 Stanley Cup odds: +50000
Perhaps the biggest move yet to be made by Chicago this summer is a contract extension for franchise center Connor Bedard, who will be a restricted free agent next summer. Other than that, GM Kyle Davidson appeared mostly content with letting his young roster develop, making no major additions.
Two children and a woman who died in a shooting in County Fermanagh have been named.
Vanessa Whyte, 45, and her two children, Sara Rutledge, aged 13, and 14-year-old James Rutledge, died in the shooting on Wednesday morning, the Police Service of Northern Ireland (PSNI) said.
A man, who is a member of the same household, was seriously injured in the shooting in the village of Maguiresbridge, about 75 miles (120km) southwest of Belfast.
Police launched a murder investigation, and Detective Chief Inspector Neil McGuinness asked people with information about the shooting incident to contact police.
Image: The scene in the Drummeer Road area of Maguiresbridge, Co Fermanagh, after three people died in a shooting. Pic: Oliver McVeigh /PA Wire
“I am particularly keen to hear from anyone who had spoken to Vanessa, Sara or James over the last few weeks. If you are someone that Vanessa, Sara or James may have confided in, please come and speak to us,” he said.
“Any information, no matter how small or insignificant it may seem could prove crucial to our investigation.”
Police don’t anticipate any arrests being made at this stage, Superintendent Robert McGowan, district commander for Fermanagh and Omagh, said at a news conference on Wednesday.
Emergency services were called to the Drummeer Road area of Maguiresbridge at around 8am on Wednesday following a report raised from the property.
Two people were found dead at the scene, and two others were seriously injured.
One patient was taken to the Royal Victoria Hospital, Belfast, by air ambulance and the other to South West Acute Hospital by ambulance. Supt McGowan said the third person died at the South West Acute Hospital.
Image: Maguiresbridge
A local Gaelic football club said the victims were all “active and beloved” members of their club.
Sara and James Rutledge also used to be part of a local cricket club, which said in a statement that it was “extremely saddened by the tragic events”.
“Both of them turned out to be talented young cricketers and two absolutely lovely-natured children,” the statement read.
Secretary of State for Northern Ireland Hilary Benn said: “The news from Maguiresbridge is tragic and deeply distressing.
“My thoughts are with the victims, their relatives and the local community in Fermanagh.”
Image: The scene was cordoned off by police following the shooting on Wednesday morning. Pic: Oliver McVeigh /PA Wire
Sinn Fein MP Pat Cullen has expressed her deep shock over the shooting.
“I’m also thinking of all the wee school friends of those two wee children and what that must feel like for all of them and how the next few days and weeks will be for everyone, particularly just at the beginning of the school holidays,” she said.
DUP MLA Deborah Erskine, who represents Co Fermanagh in the Northern Ireland Assembly, said that the community was “stunned” by the shooting in “a rural, quiet area”.
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