A potently neutralizing SARS-CoV-2 antibody inhibits variants of concern by utilizing unique binding residues in a highly conserved epitope.

With the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with increased transmissibility and potential resistance, antibodies and vaccines with broadly inhibitory activity are needed. Here, we developed a panel of neutralizing anti-SARS-CoV-2 monoclonal antibodies (mAbs) that bound the receptor binding domain of the spike protein at distinct epitopes and blocked virus attachment to its host receptor, human angiotensin converting enzyme-2 (hACE2). Although several potently neutralizing mAbs protected K18-hACE2 transgenic mice against infection caused by ancestral SARS-CoV-2 strains, others induced escape variants in vivo or lost neutralizing activity against emerging strains. One mAb, SARS2-38, potently neutralized all tested SARS-CoV-2 variants of concern and protected mice against challenge by multiple SARS-CoV-2 strains. Structural analysis showed that SARS2-38 engaged a conserved epitope proximal to the receptor binding motif. Thus, treatment with or induction of neutralizing antibodies that bind conserved spike epitopes may limit the loss of potency of therapies or vaccines against emerging SARS-CoV-2 variants.

Disease-specific alterations in the enteric virome in inflammatory bowel disease.

Decreases in the diversity of enteric bacterial populations are observed in patients with Crohn's disease (CD) and ulcerative colitis (UC). Less is known about the virome in these diseases. We show that the enteric virome is abnormal in CD and UC patients. In-depth analysis of preparations enriched for free virions in the intestine revealed that CD and UC were associated with a significant expansion of Caudovirales bacteriophages. The viromes of CD and UC patients were disease and cohort specific. Importantly, it did not appear that expansion and diversification of the enteric virome was secondary to changes in bacterial populations. These data support a model in which changes in the virome may contribute to intestinal inflammation and bacterial dysbiosis. We conclude that the virome is a candidate for contributing to, or being a biomarker for, human inflammatory bowel disease and speculate that the enteric virome may play a role in other diseases.

Natural Viruses of Caenorhabditis Nematodes.

Caenorhabditis elegans has long been a laboratory model organism with no known natural pathogens. In the past ten years, however, natural viruses have been isolated from wild-caught C. elegans (Orsay virus) and its relative Caenorhabditis briggsae (Santeuil virus, Le Blanc virus, and Melnik virus). All are RNA positive-sense viruses related to Nodaviridae; they infect intestinal cells and are horizontally transmitted. The Orsay virus capsid structure has been determined and the virus can be reconstituted by transgenesis of the host. Recent use of the Orsay virus has enabled researchers to identify evolutionarily conserved proviral and antiviral genes that function in nematodes and mammals. These pathways include endocytosis through SID-3 and WASP; a uridylyltransferase that destabilizes viral RNAs by uridylation of their 3' end; ubiquitin protein modifications and turnover; and the RNA interference pathway, which recognizes and degrades viral RNA.

Pathogenic simian immunodeficiency virus infection is associated with expansion of the enteric virome.

Pathogenic simian immunodeficiency virus (SIV) infection is associated with enteropathy, which likely contributes to AIDS progression. To identify candidate etiologies for AIDS enteropathy, we used next-generation sequencing to define the enteric virome during SIV infection in nonhuman primates. Pathogenic, but not nonpathogenic, SIV infection was associated with significant expansion of the enteric virome. We identified at least 32 previously undescribed enteric viruses during pathogenic SIV infection and confirmed their presence by using viral culture and PCR testing. We detected unsuspected mucosal adenovirus infection associated with enteritis as well as parvovirus viremia in animals with advanced AIDS, indicating the pathogenic potential of SIV-associated expansion of the enteric virome. No association between pathogenic SIV infection and the family-level taxonomy of enteric bacteria was detected. Thus, enteric viral infections may contribute to AIDS enteropathy and disease progression. These findings underline the importance of metagenomic analysis of the virome for understanding AIDS pathogenesis.

In vivo monoclonal antibody efficacy against SARS-CoV-2 variant strains.

Rapidly emerging SARS-CoV-2 variants jeopardize antibody-based countermeasures. Although cell culture experiments have demonstrated a loss of potency of several anti-spike neutralizing antibodies against variant strains of SARS-CoV-21-3, the in vivo importance of these results remains uncertain. Here we report the in vitro and in vivo activity of a panel of monoclonal antibodies (mAbs), which correspond to many in advanced clinical development by Vir Biotechnology, AbbVie, AstraZeneca, Regeneron and Lilly, against SARS-CoV-2 variant viruses. Although some individual mAbs showed reduced or abrogated neutralizing activity in cell culture against B.1.351, B.1.1.28, B.1.617.1 and B.1.526 viruses with mutations at residue E484 of the spike protein, low prophylactic doses of mAb combinations protected against infection by many variants in K18-hACE2 transgenic mice, 129S2 immunocompetent mice and hamsters, without the emergence of resistance. Exceptions were LY-CoV555 monotherapy and LY-CoV555 and LY-CoV016 combination therapy, both of which lost all protective activity, and the combination of AbbVie 2B04 and 47D11, which showed a partial loss of activity. When administered after infection, higher doses of several mAb cocktails protected in vivo against viruses with a B.1.351 spike gene. Therefore, many-but not all-of the antibody products with Emergency Use Authorization should retain substantial efficacy against the prevailing variant strains of SARS-CoV-2.

On the role of native contact cooperativity in protein folding.

The consistency of energy landscape theory predictions with available experimental data, as well as direct evidence from molecular simulations, have shown that protein folding mechanisms are largely determined by the contacts present in the native structure. As expected, native contacts are generally energetically favorable. However, there are usually at least as many energetically favorable nonnative pairs owing to the greater number of possible nonnative interactions. This apparent frustration must therefore be reduced by the greater cooperativity of native interactions. In this work, we analyze the statistics of contacts in the unbiased all-atom folding trajectories obtained by Shaw and coworkers, focusing on the unfolded state. By computing mutual cooperativities between contacts formed in the unfolded state, we show that native contacts form the most cooperative pairs, while cooperativities among nonnative or between native and nonnative contacts are typically much less favorable or even anticooperative. Furthermore, we show that the largest network of cooperative interactions observed in the unfolded state consists mainly of native contacts, suggesting that this set of mutually reinforcing interactions has evolved to stabilize the native state.

Picobirnaviruses encode proteins that are functional bacterial lysins.

Picobirnaviruses (PBVs) are double-stranded RNA viruses frequently detected in human and animal enteric viromes. Associations of PBVs with enteric graft-versus-host disease and type I diabetes during pregnancy have been established. Since their discovery in 1988, PBVs have been generally assumed to be animal-infecting viruses despite the lack of culture system, animal model, or detection in animal cells or tissues. Recent studies have proposed that bacteria or fungi could be the hosts of PBVs based on genomic analysis. Here, we functionally demonstrate that multiple PBVs of different genome organizations encode bacterial lysins that lyse Escherichia coli. Such genes are typically encoded only by bacteriophages supporting the model that PBVs infect bacterial hosts. Recognition of PBVs as RNA phages in the human gut would completely shift models of how PBVs could impact human health. In addition, expanding the RNA phage world beyond the two recognized clades to three clades has implications for our understanding of the evolution of RNA viruses.

Isolation of a recombinant simian adenovirus encoding the human adenovirus G52 hexon suggests a simian origin for human adenovirus G52.

Human adenoviruses (HAdVs) are causative agents of morbidity and mortality throughout the world. These double-stranded DNA viruses are phylogenetically classified into seven different species (A-G). HAdV-G52, originally isolated in 2008 from a patient presenting with gastroenteritis, is the sole human-derived member of species G. Phylogenetic analysis previously suggested that HAdV-G52 may have a simian origin, indicating a potential zoonotic spillover into humans. However, evidence of HAdV-G52 in either human or simian populations has not been reported since. Here, we describe the isolation and in vitro characterization of rhesus (rh)AdV-69, a novel simian AdV with clear evidence of recombination with HAdV-G52, from the stool of a rhesus macaque. Specifically, the rhAdV-69 hexon capsid protein is 100% identical to that of HAdV-G52, whereas the remainder of the genome is most similar to rhAdV-55, sharing 95.36% nucleic acid identity. A second recombination event with an unknown adenovirus (AdV) is evident at the short fiber gene. From the same sample, we also isolated a second, highly related recombinant AdV (rhAdV-68) that harbors a distinct hexon gene but nearly identical backbone compared to rhAdV-69. In vitro, rhAdV-68 and rhAdV-69 demonstrate comparable growth kinetics and tropisms in human cell lines, nonhuman cell lines, and human enteroids. Furthermore, we show that coinfection of highly related AdVs is not unique to this sample since we also isolated coinfecting rhAdVs from two additional rhesus macaque stool samples. Our data collectively contribute to elucidating the origins of HAdV-G52 and provide insights into the frequency of coinfections and subsequent recombination in AdV evolution.IMPORTANCEUnderstanding the host origins of adenoviruses (AdVs) is critical for public health as transmission of viruses from animals to humans can lead to emergent viruses. Recombination between animal and human AdVs can also produce emergent viruses. HAdV-G52 is the only human-derived member of the HAdV G species. It has been suggested that HAdV-G52 has a simian origin. Here, we isolated from a rhesus macaque, a novel rhAdV, rhAdV-69, that encodes a hexon protein that is 100% identical to that of HAdV-G52. This observation suggests that HAdV-G52 may indeed have a simian origin. We also isolated a highly related rhAdV, differing only in the hexon gene, from the same rhesus macaque stool sample as rhAdV-69, illustrating the potential for co-infection of closely related AdVs and recombination at the hexon gene. Furthermore, our study highlights the critical role of whole-genome sequencing in understanding AdV evolution and monitoring the emergence of pathogenic AdVs.

Loss of Rai1 enhances hippocampal excitability and epileptogenesis in mouse models of Smith-Magenis syndrome.

Hyperexcitability of brain circuits is a common feature of autism spectrum disorders (ASDs). Genetic deletion of a chromatin-binding protein, retinoic acid induced 1 (RAI1), causes Smith-Magenis syndrome (SMS). SMS is a syndromic ASD associated with intellectual disability, autistic features, maladaptive behaviors, overt seizures, and abnormal electroencephalogram (EEG) patterns. The molecular and neural mechanisms underlying abnormal brain activity in SMS remain unclear. Here we show that panneural Rai1 deletions in mice result in increased seizure susceptibility and prolonged hippocampal seizure duration in vivo and increased dentate gyrus population spikes ex vivo. Brain-wide mapping of neuronal activity pinpointed selective cell types within the limbic system, including the hippocampal dentate gyrus granule cells (dGCs) that are hyperactivated by chemoconvulsant administration or sensory experience in Rai1-deficient brains. Deletion of Rai1 from glutamatergic neurons, but not from gamma-aminobutyric acidergic (GABAergic) neurons, was responsible for increased seizure susceptibility. Deleting Rai1 from the Emx1Cre-lineage glutamatergic neurons resulted in abnormal dGC properties, including increased excitatory synaptic transmission and increased intrinsic excitability. Our work uncovers the mechanism of neuronal hyperexcitability in SMS by identifying Rai1 as a negative regulator of dGC intrinsic and synaptic excitability.

Highly Selective Electrochemical Baeyer-Villiger Oxidation through Oxygen Atom Transfer from Water.

The Baeyer-Villiger oxidation of ketones is a crucial oxygen atom transfer (OAT) process used for ester production. Traditionally, Baeyer-Villiger oxidation is accomplished by thermally oxidizing the OAT from stoichiometric peroxides, which are often difficult to handle. Electrochemical methods hold promise for breaking the limitation of using water as the oxygen atom source. Nevertheless, existing demonstrations of electrochemical Baeyer-Villiger oxidation face the challenges of low selectivity. We report in this study a strategy to overcome this challenge. By employing a well-known water oxidation catalyst, Fe2O3, we achieved nearly perfect selectivity for the electrochemical Baeyer-Villiger oxidation of cyclohexanone. Mechanistic studies suggest that it is essential to produce surface hydroperoxo intermediates (M-OOH, where M represents a metal center) that promote the nucleophilic attack on ketone substrates. By confining the reactions to the catalyst surfaces, competing reactions (e.g., dehydrogenation, carboxylic acid cation rearrangements, and hydroxylation) are greatly limited, thereby offering high selectivity. The surface-initiated nature of the reaction is confirmed by kinetic studies and spectroelectrochemical characterizations. This discovery adds nucleophilic oxidation to the toolbox of electrochemical organic synthesis.

A joint deep learning model enables simultaneous batch effect correction, denoising, and clustering in single-cell transcriptomics.

Recent developments of single-cell RNA-seq (scRNA-seq) technologies have led to enormous biological discoveries. As the scale of scRNA-seq studies increases, a major challenge in analysis is batch effects, which are inevitable in studies involving human tissues. Most existing methods remove batch effects in a low-dimensional embedding space. Although useful for clustering, batch effects are still present in the gene expression space, leaving downstream gene-level analysis susceptible to batch effects. Recent studies have shown that batch effect correction in the gene expression space is much harder than in the embedding space. Methods such as Seurat 3.0 rely on the mutual nearest neighbor (MNN) approach to remove batch effects in gene expression, but MNN can only analyze two batches at a time, and it becomes computationally infeasible when the number of batches is large. Here, we present CarDEC, a joint deep learning model that simultaneously clusters and denoises scRNA-seq data while correcting batch effects both in the embedding and the gene expression space. Comprehensive evaluations spanning different species and tissues showed that CarDEC outperforms Scanorama, DCA + Combat, scVI, and MNN. With CarDEC denoising, non-highly variable genes offer as much signal for clustering as the highly variable genes (HVGs), suggesting that CarDEC substantially boosted information content in scRNA-seq. We also showed that trajectory analysis using CarDEC's denoised and batch-corrected expression as input revealed marker genes and transcription factors that are otherwise obscured in the presence of batch effects. CarDEC is computationally fast, making it a desirable tool for large-scale scRNA-seq studies.

The alg-1 Gene Is Necessary for Orsay Virus Replication in Caenorhabditis elegans.

The establishment of the Orsay virus-Caenorhabditis elegans infection model has enabled the identification of host factors essential for virus infection. Argonautes are RNA interacting proteins evolutionary conserved in the three domains of life that are key components of small RNA pathways. C. elegans encodes 27 argonautes or argonaute-like proteins. Here, we determined that mutation of the argonaute-like gene 1, alg-1, results in a greater than 10,000-fold reduction in Orsay viral RNA levels, which could be rescued by ectopic expression of alg-1. Mutation in ain-1, a known interactor of ALG-1 and component of the RNA-induced silencing complex, also resulted in a significant reduction in Orsay virus levels. Viral RNA replication from an endogenous transgene replicon system was impaired by the lack of ALG-1, suggesting that ALG-1 plays a role during the replication stage of the virus life cycle. Orsay virus RNA levels were unaffected by mutations in the ALG-1 RNase H-like motif that ablate the slicer activity of ALG-1. These findings demonstrate a novel function of ALG-1 in promoting Orsay virus replication in C. elegans. IMPORTANCE All viruses are obligate intracellular parasites that recruit the cellular machinery of the host they infect to support their own proliferation. We used Caenorhabditis elegans and its only known infecting virus, Orsay virus, to identify host proteins relevant for virus infection. We determined that ALG-1, a protein previously known to be important in influencing worm life span and the expression levels of thousands of genes, is required for Orsay virus infection of C. elegans. This is a new function attributed to ALG-1 that was not recognized before. In humans, it has been shown that AGO2, a close relative protein to ALG-1, is essential for hepatitis C virus replication. This demonstrates that through evolution from worms to humans, some proteins have maintained similar functions, and consequently, this suggests that studying virus infection in a simple worm model has the potential to provide novel insights into strategies used by viruses to proliferate.

The Highly Conserved Stem-Loop II Motif Is Dispensable for SARS-CoV-2.

The stem-loop II motif (s2m) is an RNA structural element that is found in the 3' untranslated region (UTR) of many RNA viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Though the motif was discovered over 25 years ago, its functional significance is unknown. In order to understand the importance of s2m, we created viruses with deletions or mutations of the s2m by reverse genetics and also evaluated a clinical isolate harboring a unique s2m deletion. Deletion or mutation of the s2m had no effect on growth in vitro or on growth and viral fitness in Syrian hamsters in vivo. We also compared the secondary structure of the 3' UTR of wild-type and s2m deletion viruses using selective 2'-hydroxyl acylation analyzed by primer extension and mutational profiling (SHAPE-MaP) and dimethyl sulfate mutational profiling and sequencing (DMS-MaPseq). These experiments demonstrate that the s2m forms an independent structure and that its deletion does not alter the overall remaining 3'-UTR RNA structure. Together, these findings suggest that s2m is dispensable for SARS-CoV-2. IMPORTANCE RNA viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), contain functional structures to support virus replication, translation, and evasion of the host antiviral immune response. The 3' untranslated region of early isolates of SARS-CoV-2 contained a stem-loop II motif (s2m), which is an RNA structural element that is found in many RNA viruses. This motif was discovered over 25 years ago, but its functional significance is unknown. We created SARS-CoV-2 with deletions or mutations of the s2m and determined the effect of these changes on viral growth in tissue culture and in rodent models of infection. Deletion or mutation of the s2m element had no effect on growth in vitro or on growth and viral fitness in Syrian hamsters in vivo. We also observed no impact of the deletion on other known RNA structures in the same region of the genome. These experiments demonstrate that s2m is dispensable for SARS-CoV-2.

Optimization of a mouse model of pancreatic cancer to simulate the human phenotypes of metastasis and cachexia.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) presents with a high mortality rate. Two important features of PDAC contribute to this poor outcome. The first is metastasis which occurs in ~ 80% of PDAC patients. The second is cachexia, which compromises treatment tolerance for patients and reduces their quality of life. Although various mouse models of PDAC exist, recapitulating both metastatic and cachectic features have been challenging. METHODS: Here, we optimize an orthotopic mouse model of PDAC by altering several conditions, including the subcloning of parental murine PDAC cells, implantation site, number of transplanted cells, and age of recipient mice. We perform spatial profiling to compare primary and metastatic immune microenvironments and RNA sequencing to gain insight into the mechanisms of muscle wasting in PDAC-induced cachexia, comparing non-metastatic to metastatic conditions. RESULTS: These modifications extend the time course of the disease and concurrently increase the rate of metastasis to approximately 70%. Furthermore, reliable cachexia endpoints are achieved in both PDAC mice with and without metastases, which is reminiscent of patients. We also find that cachectic muscles from PDAC mice with metastasis exhibit a similar transcriptional profile to muscles derived from mice and patients without metastasis. CONCLUSION: Together, this model is likely to be advantageous in both advancing our understanding of the mechanism of PDAC cachexia, as well as in the evaluation of novel therapeutics.

Ocular manifestations of the genetic causes of focal and segmental glomerulosclerosis.

Genetic forms of focal and segmental glomerulosclerosis (FSGS) often have extra-renal manifestations. This study examined FSGS-associated genes from the Genomics England Renal proteinuria panel for reported and likely ocular features. Thirty-two of the 55 genes (58%) were associated with ocular abnormalities in human disease, and a further 12 (22%) were expressed in the retina or had an eye phenotype in mouse models. The commonest genes affected in congenital nephrotic syndrome (NPHS1, NPHS2, WT1, LAMB2, PAX2 but not PLCE1) may have ocular manifestations . Many genes affected in childhood-adolescent onset FSGS (NPHS1, NPHS2, WT1, LAMB2, SMARCAL1, NUP107 but not TRPC6 or PLCE1) have ocular features. The commonest genes affected in adult-onset FSGS (COL4A3-COL4A5, GLA ) have ocular abnormalities but not the other frequently affected genes (ACTN4, CD2AP, INF2, TRPC6). Common ocular associations of genetic FSGS include cataract, myopia, strabismus, ptosis and retinal atrophy. Mitochondrial forms of FSGS (MELAS, MIDD, Kearn's Sayre disease) are associated with retinal atrophy and inherited retinal degeneration. Some genetic kidney diseases (CAKUT, ciliopathies, tubulopathies) that result in secondary forms of FSGS also have ocular features. Ocular manifestations suggest a genetic basis for FSGS, often help identify the affected gene, and prompt genetic testing. In general, ocular abnormalities require early evaluation by an ophthalmologist, and sometimes, monitoring or treatment to improve vision or prevent visual loss from complications. In addition, the patient should be examined for other syndromic features and first degree family members assessed.

Machine learning classifiers for electrode selection in the design of closed-loop neuromodulation devices for episodic memory improvement.

Successful neuromodulation approaches to alter episodic memory require closed-loop stimulation predicated on the effective classification of brain states. The practical implementation of such strategies requires prior decisions regarding electrode implantation locations. Using a data-driven approach, we employ support vector machine (SVM) classifiers to identify high-yield brain targets on a large data set of 75 human intracranial electroencephalogram subjects performing the free recall (FR) task. Further, we address whether the conserved brain regions provide effective classification in an alternate (associative) memory paradigm along with FR, as well as testing unsupervised classification methods that may be a useful adjunct to clinical device implementation. Finally, we use random forest models to classify functional brain states, differentiating encoding versus retrieval versus non-memory behavior such as rest and mathematical processing. We then test how regions that exhibit good classification for the likelihood of recall success in the SVM models overlap with regions that differentiate functional brain states in the random forest models. Finally, we lay out how these data may be used in the design of neuromodulation devices.

Optimal sample selection applied to information rich, dense data.

Dense data can be classified into superdense information-poor data (type 1 dense data) and dense information-rich data (type 2 dense data). Arbitrary, random, or optimal thinning may be applied to type 1 dense data to minimise computational burden and statistical issues (such as autocorrelation). In contrast, a prospective or retrospective optimal design can be applied to type 2 dense data to maximise information gain from limited resources (capital and/or time). Here we describe a retrospective optimal selection strategy for quantification of unbound drug concentration from a discrete set of plasma samples where the total drug concentration has been measured.

Oral docetaxel plus encequidar - A pharmacokinetic model and evaluation against IV docetaxel.

The development of optimized dosing regimens plays a crucial role in oncology drug development. This study focused on the population pharmacokinetic modelling and simulation of docetaxel, comparing the pharmacokinetic exposure of oral docetaxel plus encequidar (oDox + E) with the standard of care intravenous (IV) docetaxel regimen. The aim was to evaluate the feasibility of oDox + E as a potential alternative to IV docetaxel. The article demonstrates an approach which aligns with the FDA's Project Optimus which aims to improve oncology drug development through model informed drug development (MIDD). The key question answered by this study was whether a feasible regimen of oDox + E existed. The purpose of this question was to provide an early GO / NO-GO decision point to guide drug development and improve development efficiency. METHODS:  A stepwise approach was employed to develop a population pharmacokinetic model for total and unbound docetaxel plasma concentrations after IV docetaxel and oDox + E administration. Simulations were performed from the final model to assess the probability of target attainment (PTA) for different oDox + E dose regimens (including multiple dose regimens) in relation to IV docetaxel using AUC over effective concentration (AUCOEC) metric across a range of effective concentrations (EC). A Go / No-Go framework was defined-the first part of the framework assessed whether a feasible oDox + E regimen existed (i.e., a PTA ≥ 80%), and the second part defined the conditions to proceed with a Go decision. RESULTS:  The overall population pharmacokinetic model consisted of a 3-compartment model with linear elimination, constant bioavailability, constant binding mechanics, and a combined error model. Simulations revealed that single dose oDox + E regimens did not achieve a PTA greater than 80%. However, two- and three-dose regimens at 600 mg achieved PTAs exceeding 80% for certain EC levels. CONCLUSION:  The study demonstrates the benefits of MIDD using oDox + E as a motivating example. A population pharmacokinetic model was developed for the total and unbound concentration in plasma of docetaxel after administration of IV docetaxel and oDox + E. The model was used to simulate oDox + E dose regimens which were compared to the current standard of care IV docetaxel regimen. A GO / NO-GO framework was applied to determine whether oDox + E should progress to the next phase of drug development and whether any conditions should apply. A two or three-dose regimen of oDox + E at 600 mg was able to achieve non-inferior pharmacokinetic exposure to current standard of care IV docetaxel in simulations. A Conditional GO decision was made based on this result and further quantification of the "effective concentration" would improve the ability to optimise the dose regimen.

Dyslipidaemia is associated with Cutibacterium acnes hip and knee prosthetic joint infection.

PURPOSE: Optimization of medical factors including diabetes and obesity is a cornerstone in the prevention of prosthetic joint infection (PJI). Dyslipidaemia is another component of metabolic syndrome which has not been thoroughly investigated as an individual, modifiable risk factor. This study examined the association of dyslipidaemia with PJI caused by the lipophilic microbe Cutibacterium acnes (C. acnes). METHODS: A retrospective chart review examined patients with positive C. acnes culture at hip or knee arthroplasty explantation. A control group with methicillin-sensitive Staphylococcus aureus (MSSA) positive cultures at explantation was matched for age, sex, and surgical site, as well as a second control group with no infection. A total of 80 patients were included, 16 with C. acnes, 32 with MSSA, and 32 with no infection. All patients had a lipid panel performed within one year of surgery. Lipid values and categories were compared using multinomial logistic regressions. RESULTS: High or borderline triglycerides (TG) (relative risk ratio (RRR) = 0.13; P = 0.013) and low high-density lipoprotein (HDL) (RRR = 0.13; P = 0.025) were significantly associated with C. acnes PJI compared to MSSA-PJI. High or borderline TG (RRR = 0.21; P = 0.041) and low HDL (RRR = 0.17; P = 0.043) were also associated with a greater probability of C. acnes infection compared to no infection. CONCLUSIONS: The presence of elevated TG and low HDL were both associated at a statistically significant level with C. acnes hip or knee PJI compared to controls with either MSSA PJI or no infection. This may represent a specific risk factor for C. acnes PJI that is modifiable.