{"id":29581,"date":"2024-07-29T12:25:50","date_gmt":"2024-07-29T16:25:50","guid":{"rendered":"https:\/\/biology.mit.edu\/?p=29581"},"modified":"2024-08-01T12:45:24","modified_gmt":"2024-08-01T16:45:24","slug":"news-brief-lamason-lab-uncovers-seven-novel-effectors-in-rickettsia-parkeri-infection","status":"publish","type":"post","link":"https:\/\/biology.mit.edu\/news-brief-lamason-lab-uncovers-seven-novel-effectors-in-rickettsia-parkeri-infection\/","title":{"rendered":"News Brief: Lamason Lab uncovers seven novel effectors in Rickettsia parkeri infection"},"content":{"rendered":"

Identifying secreted proteins is critical to understanding how obligately intracellular pathogens hijack host machinery during infection, but identifying them is akin to finding a needle in a haystack.<\/span><\/h3>\n

For then-graduate student Allen Sanderlin, PhD \u201924, the first indication that a risky, unlikely project might work was cyan, tic tac-shaped structures seen through a microscope \u2014 proof that his bacterial pathogen of interest was labeling its own proteins.\u00a0\u00a0<\/span><\/p>\n

Sanderlin, a member of the Lamason Lab in the Department of Biology at MIT, studies <\/span>Rickettsia parkeri<\/span><\/i>, a less virulent relative of the bacterial pathogen that causes <\/span>Rocky Mountain Spotted Fever<\/span><\/a>, a sometimes severe tickborne illness. No vaccine exists and definitive tests to diagnose an infection by <\/span>Rickettsia <\/span><\/i>are limited<\/span>.<\/span><\/i><\/p>\n

Rickettsia<\/span><\/i> species are tricky to work with because they are obligately intracellular pathogens whose entire life cycles occur exclusively inside cells. Many approaches that have advanced our understanding of other bacterial infections and how those pathogens interact with their host aren\u2019t applicable to <\/span>Rickettsia <\/span><\/i>because they can\u2019t be grown on a plate in a lab setting.\u00a0<\/span><\/p>\n

In a paper recently published in <\/span>Nature Communications<\/span><\/i><\/a>, the Lamason Lab outlines an approach for labeling and isolating <\/span>R. parkeri<\/span><\/i> proteins released during infection. This research reveals seven previously unknown secreted factors, known as effectors, more than doubling the number of known effectors in <\/span>R. parkeri.\u00a0<\/span><\/i><\/p>\n

Better-studied bacteria are known to hijack the host\u2019s machinery via dozens or hundreds of secreted effectors, whose roles include manipulating the host cell to make it more susceptible to infection. However, finding those effectors in the soup of all other materials within the host cell is akin to looking for a needle in a haystack, with an added twist that researchers aren\u2019t even sure what those needles look like for <\/span>Rickettsia.\u00a0\u00a0<\/span><\/i><\/p>\n

Approaches that worked to identify the six previously known secreted effectors are limited in their scope. For example, some were found by comparing pathogenic <\/span>Rickettsia<\/span><\/i> to nonpathogenic strains of the bacteria, or by searching for proteins with domains that overlap NetBet sportwith effectors from better-studied bacteria. Predictive modeling, however, relies on proteins being evolutionarily conserved.\u00a0<\/span><\/p>\n

\u201cTime and time again, we keep finding that <\/span>Rickettsia<\/span><\/i> are just weird \u2014 or, at least, weird compared to our understanding of other bacteria,\u201d says Sanderlin, the paper’s first author. \u201cThis labeling tool allows us to answer some really exciting questions about rickettsial biology that weren\u2019t possible before.\u201d<\/span><\/p>\n

The cyan tic tacs<\/h2>\n

To selectively label <\/span>R. parkeri <\/span><\/i>proteins, Sanderlin used a method called cell-selective bioorthogonal non-canonical amino acid tagging. <\/span>BONCAT was first described<\/span><\/a> in research from the <\/span>Tirrell Lab at Caltech<\/span><\/a>. The Lamason Lab, however, is the first group to use the tool successfully in an obligate intracellular bacterial pathogen; the thrilling moment when Sanderlin saw cyan tic-tac shapes indicated successfully labeling only the pathogen, not the host.\u00a0<\/span><\/p>\n

Sanderlin next used an approach called selective lysis, carefully breaking open the host cell while leaving the pathogen, filled with labeled proteins, intact. This allowed him to extract proteins that <\/span>R. parkeri<\/span><\/i> had released into its host because the only labeled proteins amid other host cell material were effectors the pathogen had secreted.\u00a0<\/span><\/p>\n

Sanderlin had successfully isolated and identified seven needles in the haystack, effectors never before identified in <\/span>Rickettsia<\/span><\/i> biology. The novel secreted rickettsial factors are dubbed SrfA, SrfB, SrfC, SrfD, SrfE, SrfF, and SrfG.\u00a0<\/span><\/p>\n

\u201cEvery grad student wants to be able to name something,\u201d Sanderlin says. \u201cThe most exciting \u2014 but frustrating \u2014 thing was that these proteins don\u2019t look like anything we\u2019ve seen before.\u201d<\/span><\/p>\n

Special delivery<\/h2>\n

Theoretically, Sanderlin says, once the effectors are secreted, they work independently from the bacteria \u2014 a driver delivering a pizza does not need to check back in with the store at every merge or turn.<\/span><\/p>\n

Since SrfA-G didn\u2019t resemble other known effectors or host proteins the pathogen could be mimicking during infection, Sanderlin then tried to answer some basic questions about their behavior. Where the effectors localize, meaning where in the cell they go, could hint at their purpose and what further experiments could be used to investigate it.\u00a0<\/span><\/p>\n

To determine where the effectors were going, Sanderlin added the effectors he\u2019d found to uninfected cells by introducing DNA that caused human cell lines to express those proteins. The experiment succeeded: he discovered that different Srfs went to different places throughout the host cells.\u00a0\u00a0<\/span><\/p>\n

SrfF and SrfG are found throughout the cytoplasm, whereas SrfB localizes to the mitochondria. That was especially intriguing because its structure is not predicted to interact with or find its way to the mitochondria, and the organelle appears unchanged despite the presence of the effector.\u00a0<\/span><\/p>\n

Further, SrfC and SrfD found their way to the endoplasmic reticulum. The ER would be especially useful for a pathogen to appropriate, given that it is a dynamic organelle present throughout the cell and has many essential roles, including synthesizing proteins and metabolizing lipids.\u00a0<\/span><\/p>\n

Aside from where effectors localize, knowing what they may interact with is critical. Sanderlin showed that SrfD interacts with Sec61, a protein complex that delivers proteins across the ER membrane. In keeping with the theme of the novelty of Sanderlin\u2019s findings, SrfD does not resemble any proteins known to interact with the ER or Sec61.\u00a0<\/span><\/p>\n

With this tool, Sanderlin identified novel proteins whose binding partners and role during infection can now be studied further.\u00a0<\/span><\/p>\n

\u201cThese results are exciting but tantalizing,\u201d Sanderlin says. \u201cWhat <\/span>Rickettsia<\/span><\/i> secrete \u2014 the effectors, what they are, and what they do is, by and large, still a black box.\u201d\u00a0<\/span><\/p>\n

There are very likely other effectors in the proverbial cellular haystack. Sanderlin found that SrfA-G are not found in every species of <\/span>Rickettsia,<\/span><\/i> and his experiments were solely conducted with <\/span>Rickettsia<\/span><\/i> at late stages of infection \u2014 earlier windows of time may make use of different effectors. This research was also carried out in human cell lines, so there may be an entirely separate repertoire of effectors in ticks, which are responsible for spreading the pathogen.<\/span><\/p>\n

Expanding Tool Development<\/h2>\n

Becky Lamason, the senior author of the <\/span>Nature Communications <\/span><\/i>paper, noted that this tool is one of a few avenues the lab is exploring to investigate <\/span>R. parkeri<\/span><\/i>, including <\/span>a paper in the Journal of Bacteriology<\/span><\/a> on conditional genetic manipulation. Characterizing how the pathogen behaves with or without a particular effector is leaps and bounds ahead of where the field was just a few years ago when Sanderlin was Lamason\u2019s first graduate student to join the lab.<\/span><\/p>\n

\u201cWhat I always hoped for in the lab is to push the technology, but also get to the biology. These are two of what will hopefully be a suite of ways to attack this problem of understanding how these bacteria rewire and manipulate the host cell,\u201d Lamason says. \u201cWe\u2019re excited, but we\u2019ve only scratched the surface.\u201d<\/span><\/p>\n","protected":false},"excerpt":{"rendered":"

Identifying secreted proteins is critical to understanding how obligately intracellular pathogens hijack host machinery during infection, but identifying them is akin to finding a needle in a haystack. For then-graduate student Allen Sanderlin, PhD \u201924, the first indication that a risky, unlikely project might work was cyan, tic tac-shaped structures seen through a microscope \u2014 […]<\/p>\n","protected":false},"author":1783,"featured_media":29586,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":""},"categories":[6253,6224,6212],"tags":[],"class_list":["post-29581","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-building-68-faculty-locations","category-building-68-news-briefs","category-news-briefs"netbet sports betting,"placement-placement-homepage","research-area-biochemistry-biophysics-and-structural-biology","research-area-cell-biology","research-area-microbiology"],"acf":[],"yoast_head":"\nNews Brief: Lamason Lab uncovers seven novel effectors in Rickettsia parkeri infection - MIT Department of Biology<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/biology.mit.edu\/news-brief-lamason-lab-uncovers-seven-novel-effectors-in-rickettsia-parkeri-infection\/\" \/>\n<meta property=\"og:locale\" content=\"en_US\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"News Brief: Lamason Lab uncovers seven novel effectors in Rickettsia parkeri infection\" \/>\n<meta property=\"og:description\" content=\"Identifying secreted proteins is critical to understanding how obligately intracellular pathogens hijack host machinery during infection, but identifying them is akin to finding a needle in a haystack. 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