The IRG1-itaconate axis protects from cholesterol-induced inflammation and atherosclerosis.

Atherosclerosis is fueled by a failure to resolve lipid-driven inflammation within the vasculature that drives plaque formation. Therapeutic approaches to reverse atherosclerotic inflammation are needed to address the rising global burden of cardiovascular disease (CVD). Recently, metabolites have gained attention for their immunomodulatory properties, including itaconate, which is generated from the tricarboxylic acid-intermediate cis-aconitate by the enzyme Immune Responsive Gene 1 (IRG1/ACOD1). Here, we tested the therapeutic potential of the IRG1-itaconate axis for human atherosclerosis. Using single-cell RNA sequencing (scRNA-seq), we found that IRG1 is up-regulated in human coronary atherosclerotic lesions compared to patient-matched healthy vasculature, and in mouse models of atherosclerosis, where it is primarily expressed by plaque monocytes, macrophages, and neutrophils. Global or hematopoietic Irg1-deficiency in mice increases atherosclerosis burden, plaque macrophage and lipid content, and expression of the proatherosclerotic cytokine interleukin (IL)-1ß. Mechanistically, absence of Irg1 increased macrophage lipid accumulation, and accelerated inflammation via increased neutrophil extracellular trap (NET) formation and NET-priming of the NLRP3-inflammasome in macrophages, resulting in increased IL-1ß release. Conversely, supplementation of the Irg1-itaconate axis using 4-octyl itaconate (4-OI) beneficially remodeled advanced plaques and reduced lesional IL-1ß levels in mice. To investigate the effects of 4-OI in humans, we leveraged an ex vivo systems-immunology approach for CVD drug discovery. Using CyTOF and scRNA-seq of peripheral blood mononuclear cells treated with plasma from CVD patients, we showed that 4-OI attenuates proinflammatory phospho-signaling and mediates anti-inflammatory rewiring of macrophage populations. Our data highlight the relevance of pursuing IRG1-itaconate axis supplementation as a therapeutic approach for atherosclerosis in humans.

Taxanes for the treatment of breast cancer during pregnancy: an international cohort study.

INTRODUCTION: The addition of taxanes to anthracycline-based chemotherapy is considered standard of care in the treatment of breast cancer. However, there are insufficient data regarding the safety of taxanes during pregnancy. The aim of this study was to describe the incidence of obstetric and neonatal adverse events associated with the use of taxane-containing chemotherapy regimens for the treatment of breast cancer during pregnancy. METHODS: This is a multicenter, international cohort study of breast cancer patients treated with taxanes during pregnancy. A descriptive analysis was undertaken to synthetize available data. RESULTS: A total of 103 patients were included, most of whom were treated with paclitaxel and anthracyclines given in sequence during gestation (90.1%). The median gestational age at taxane initiation was 28 weeks (range = 12-37 weeks). Grade 3-4 adverse events were reported in 7 of 103 (6.8%) patients. The most common reported obstetric complications were intrauterine growth restriction (n = 8 of 94, 8.5%) and preterm premature rupture of membranes (n = 5 of 94, 5.3%). The live birth rate was 92 of 94 (97.9%), and the median gestational age at delivery was 37 weeks (range = 32-40 weeks). Admission to an intensive care unit was reported in 14 of 88 (15.9%) neonates, and 17 of 70 (24.3%) live births resulted in small for gestational age neonates. Congenital malformations were reported in 2 of 93 (2.2%). CONCLUSION: Obstetric and neonatal outcomes after taxane exposure during pregnancy were generally favorable and did not seem to differ from those reported in the literature with standard anthracycline-based regimens. This study supports the use of taxanes during gestation when clinically indicated.

Tailoring Treatment for Patients with Inflammatory Breast Cancer.

OPINION STATEMENT: Inflammatory breast cancer (IBC) is a rare but aggressive subtype of breast cancer that has a propensity for locoregional recurrence and distant metastasis and is associated with a disproportionately high percentage of breast cancer deaths. IBC is not resectable at initial diagnosis and trimodality therapy is considered the standard treatment for IBC. This includes systemic therapy upfront, followed by modified radical mastectomy and comprehensive chest wall and regional node radiation. Despite this aggressive multi-modal treatment strategy, the prognosis remains worse in IBC when compared with non-inflammatory locally advanced breast cancers. For patients presenting with de novo stage IV IBC, treatment recommendations vary depending on tumor burden, cancer subtype, and presence of comorbidities. Efforts to improve outcomes in IBC are currently underway; however, progress has been affected by the low incidence of disease and limited number of dedicated studies in this population. Improvements in systemic therapies in breast cancer in general are likely to lead to improvements in IBC as well. More dedicated trials are needed to identify additional treatment strategies that may help to improve prognosis for these patients. Additionally, better frameworks for diagnosis, risk stratification based upon factors such as molecular subtype and response to neoadjuvant therapy, will be important to make further progress in IBC.

A one-health review on brucellosis in the United States.

Brucellosis is a highly infectious zoonotic disease of global significance due to its adverse impact on public health, economics, and trade. Despite being one of the most prevalent zoonoses worldwide, attention given to global brucellosis control and prevention has been inadequate. Brucella species of greatest one-health relevance in the US include those infecting dogs (Brucella canis), swine (Brucella suis), and cattle and domestic bison (Brucella abortus). Although not endemic in the US, Brucella melitensis warrants awareness as it poses a risk to international travelers. While brucellosis has been eradicated from domestic livestock in the US, its detection in US companion animals (B canis) and US wildlife reservoirs (B suis and B abortus) and enzootic presence internationally pose a threat to human and animal health, warranting its spotlight on the one-health stage. The challenges of B canis diagnosis in humans and dogs is addressed in more detail in the companion Currents in One Health by Guarino et al, AJVR, April 2023. Human consumption of unpasteurized dairy products and occupational exposure of laboratory diagnosticians, veterinarians, and animal care providers are responsible for human exposures reported to the US CDC. Diagnosis and treatment of brucellosis is challenging due to the limitations of diagnostic assays and the tendency of Brucella spp to produce nonspecific, insidious clinical signs and evade antimicrobial therapy, making prevention essential. This review will focus on zoonotic considerations for Brucella spp found within the US along with their epidemiology, pathophysiology, clinical presentation, treatment, and control strategies.

Recent Incarceration Among Individuals Infected With Hepatitis A Virus During Person-to-Person Community Outbreaks, United States, 2016-2020.

OBJECTIVES: Although many people who are incarcerated have risk factors for hepatitis A virus (HAV) infection, the proportion of hepatitis A cases among people with a recent incarceration is unknown. We examined the relationship between recent incarceration and HAV infection during community-based, person-to-person outbreaks to inform public health recommendations. METHODS: The Centers for Disease Control and Prevention surveyed health departments in 33 jurisdictions reporting person-to-person HAV outbreaks during 2016-2020 on the number of outbreak-associated cases, HAV-infected people recently incarcerated, and HAV-associated hospitalizations and deaths. RESULTS: Twenty-five health departments reported 18 327 outbreak-associated hepatitis A cases during January 11, 2016-January 24, 2020. In total, 2093 (11.4%) HAV-infected people had been recently incarcerated. Of those with complete data, 1402 of 1462 (95.9%) had been held in a local jail, and 1513 of 1896 (79.8.%) disclosed hepatitis A risk factors. Eighteen jurisdictions reported incarceration timing relative to the exposure period. Of 9707 cases in these jurisdictions, 991 (10.2%) were among recently incarcerated people; 451 of 688 (65.6%) people with complete data had been incarcerated during all (n = 55) or part (n = 396) of their exposure period. CONCLUSIONS: Correctional facilities are important settings for reaching people with risk factors for HAV infection and can also be venues where transmission occurs. Providing HAV vaccination to incarcerated people, particularly people housed in jails, can be an effective component of community-wide outbreak response.

A custom hepatitis A virus assay for whole-genome sequencing.

Since 2016, the United States has experienced a resurgence in the number of hepatitis A virus (HAV) cases and outbreaks. These outbreaks have been sustained by person-to-person transmission with cases occurring predominantly in high-risk populations including intravenous drug users, individuals experiencing homelessness, and men who have sex with men. To investigate HAV transmission, a molecular-surveillance system consisting of real-time RT-PCR (rRT-PCR) for detection, and a conventional RT-PCR assay for genotyping of HAV, was established in New York State (NYS) in 2019. Since then, a total of 271 HAV-positive serum samples collected from cases across NYS between 2019 and 2021 were identified by rRT-PCR. To rapidly and efficiently generate HAV whole-genome sequences, a custom AmpliSeq™ panel was designed in collaboration with Thermo Fisher. To streamline the process, sample preparation was performed on an Ion Chef and sequencing on an Ion S5XL. Of the 271 HAV-positive samples, the whole-genome sequencing (WGS) assay successfully generated 134 near-complete, high-quality HAV sequences. Phylogenetic analysis of the VP1-2A region identified 216 IB, 48 IA, and 2 IIIA genotypes, while 5 were unable to be typed due to poor sequence in this key region. The HAV whole-genome sequencing approach provided a more efficient and streamlined approach for genotyping HAV compared to previous methods and resulted in phylogenetic trees with enhanced resolution compared to the HAV VP1-2A region alone.

Monkeypox in a Young Infant - Florida, 2022.

In August 2022, the Florida Department of Health (FDOH) was notified of a suspected case of monkeypox in an infant aged <2 months who was admitted to a Florida hospital with a rash and cellulitis. This case report highlights findings from the related epidemiologic investigation and describes the public health actions taken. This activity was reviewed by CDC and was conducted consistent with applicable federal law and CDC policy.* This is the youngest patient with confirmed monkeypox infection in Florida to date.

Epidemiologic and Clinical Characteristics of Monkeypox Cases - United States, May 17-July 22, 2022.

Monkeypox, a zoonotic infection caused by an orthopoxvirus, is endemic in parts of Africa. On August 4, 2022, the U.S. Department of Health and Human Services declared the U.S. monkeypox outbreak, which began on May 17, to be a public health emergency (1,2). After detection of the first U.S. monkeypox case), CDC and health departments implemented enhanced monkeypox case detection and reporting. Among 2,891 cases reported in the United States through July 22 by 43 states, Puerto Rico, and the District of Columbia (DC), CDC received case report forms for 1,195 (41%) cases by July 27. Among these, 99% of cases were among men; among men with available information, 94% reported male-to-male sexual or close intimate contact during the 3 weeks before symptom onset. Among the 88% of cases with available data, 41% were among non-Hispanic White (White) persons, 28% among Hispanic or Latino (Hispanic) persons, and 26% among non-Hispanic Black or African American (Black) persons. Forty-two percent of persons with monkeypox with available data did not report the typical prodrome as their first symptom, and 46% reported one or more genital lesions during their illness; 41% had HIV infection. Data suggest that widespread community transmission of monkeypox has disproportionately affected gay, bisexual, and other men who have sex with men and racial and ethnic minority groups. Compared with historical reports of monkeypox in areas with endemic disease, currently reported outbreak-associated cases are less likely to have a prodrome and more likely to have genital involvement. CDC and other federal, state, and local agencies have implemented response efforts to expand testing, treatment, and vaccination. Public health efforts should prioritize gay, bisexual, and other men who have sex with men, who are currently disproportionately affected, for prevention and testing, while addressing equity, minimizing stigma, and maintaining vigilance for transmission in other populations. Clinicians should test patients with rash consistent with monkeypox,† regardless of whether the rash is disseminated or was preceded by prodrome. Likewise, although most cases to date have occurred among gay, bisexual, and other men who have sex with men, any patient with rash consistent with monkeypox should be considered for testing. CDC is continually evaluating new evidence and tailoring response strategies as information on changing case demographics, clinical characteristics, transmission, and vaccine effectiveness become available.§.

Multistate Outbreak of SARS-CoV-2 Infections, Including Vaccine Breakthrough Infections, Associated with Large Public Gatherings, United States.

During July 2021, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) B.1.617.2 variant infections, including vaccine breakthrough infections, occurred after large public gatherings in Provincetown, Massachusetts, USA, prompting a multistate investigation. Public health departments identified primary and secondary cases by using coronavirus disease surveillance data, case investigations, and contact tracing. A primary case was defined as SARS-CoV-2 detected <14 days after travel to or residence in Provincetown during July 3-17. A secondary case was defined as SARS-CoV-2 detected <14 days after close contact with a person who had a primary case but without travel to or residence in Provincetown during July 3-August 10. We identified 1,098 primary cases and 30 secondary cases associated with 26 primary cases among fully and non-fully vaccinated persons. Large gatherings can have widespread effects on SARS-CoV-2 transmission, and fully vaccinated persons should take precautions, such as masking, to prevent SARS-CoV-2 transmission, particularly during substantial or high transmission.

SMC-Derived Hyaluronan Modulates Vascular SMC Phenotype in Murine Atherosclerosis.

[Figure: see text].

Chronic stress primes innate immune responses in mice and humans.

Psychological stress (PS) is associated with systemic inflammation and accelerates inflammatory disease progression (e.g., atherosclerosis). The mechanisms underlying stress-mediated inflammation and future health risk are poorly understood. Monocytes are key in sustaining systemic inflammation, and recent studies demonstrate that they maintain the memory of inflammatory insults, leading to a heightened inflammatory response upon rechallenge. We show that PS induces remodeling of the chromatin landscape and transcriptomic reprogramming of monocytes, skewing them to a primed hyperinflammatory phenotype. Monocytes from stressed mice and humans exhibit a characteristic inflammatory transcriptomic signature and are hyperresponsive upon stimulation with Toll-like receptor ligands. RNA and ATAC sequencing reveal that monocytes from stressed mice and humans exhibit activation of metabolic pathways (mTOR and PI3K) and reduced chromatin accessibility at mitochondrial respiration-associated loci. Collectively, our findings suggest that PS primes the reprogramming of myeloid cells to a hyperresponsive inflammatory state, which may explain how PS confers inflammatory disease risk.

Silencing Myeloid Netrin-1 Induces Inflammation Resolution and Plaque Regression.

[Figure: see text].

Multiple cell types contribute to the atherosclerotic lesion fibrous cap by PDGFRß and bioenergetic mechanisms.

Stable atherosclerotic plaques are characterized by a thick, extracellular matrix-rich fibrous cap populated by protective ACTA2+ myofibroblast (MF)-like cells, assumed to be almost exclusively derived from smooth muscle cells (SMCs). Herein, we show that in murine and human lesions, 20% to 40% of ACTA2+ fibrous cap cells, respectively, are derived from non-SMC sources, including endothelial cells (ECs) or macrophages that have undergone an endothelial-to-mesenchymal transition (EndoMT) or a macrophage-to-mesenchymal transition (MMT). In addition, we show that SMC-specific knockout of the Pdgfrb gene, which encodes platelet-derived growth factor receptor beta (PDGFRß), in Apoe-/- mice fed a Western diet for 18 weeks resulted in brachiocephalic artery lesions nearly devoid of SMCs but with no changes in lesion size, remodelling or indices of stability, including the percentage of ACTA2+ fibrous cap cells. However, prolonged Western diet feeding of SMC Pdgfrb-knockout mice resulted in reduced indices of stability, indicating that EndoMT- and MMT-derived MFs cannot compensate indefinitely for loss of SMC-derived MFs. Using single-cell and bulk RNA-sequencing analyses of the brachiocephalic artery region and in vitro models, we provide evidence that SMC-to-MF transitions are induced by PDGF and transforming growth factor-ß and dependent on aerobic glycolysis, while EndoMT is induced by interleukin-1ß and transforming growth factor-ß. Together, we provide evidence that the ACTA2+ fibrous cap originates from a tapestry of cell types, which transition to an MF-like state through distinct signalling pathways that are either dependent on or associated with extensive metabolic reprogramming.

Myocardial infarction accelerates breast cancer via innate immune reprogramming.

Disruption of systemic homeostasis by either chronic or acute stressors, such as obesity1 or surgery2, alters cancer pathogenesis. Patients with cancer, particularly those with breast cancer, can be at increased risk of cardiovascular disease due to treatment toxicity and changes in lifestyle behaviors3-5. While elevated risk and incidence of cardiovascular events in breast cancer is well established, whether such events impact cancer pathogenesis is not known. Here we show that myocardial infarction (MI) accelerates breast cancer outgrowth and cancer-specific mortality in mice and humans. In mouse models of breast cancer, MI epigenetically reprogrammed Ly6Chi monocytes in the bone marrow reservoir to an immunosuppressive phenotype that was maintained at the transcriptional level in monocytes in both the circulation and tumor. In parallel, MI increased circulating Ly6Chi monocyte levels and recruitment to tumors and depletion of these cells abrogated MI-induced tumor growth. Furthermore, patients with early-stage breast cancer who experienced cardiovascular events after cancer diagnosis had increased risk of recurrence and cancer-specific death. These preclinical and clinical results demonstrate that MI induces alterations in systemic homeostasis, triggering cross-disease communication that accelerates breast cancer.

First Reported Cases of SARS-CoV-2 Infection in Companion Animals - New York, March-April 2020.

On April 22, CDC and the U.S. Department of Agriculture (USDA) reported cases of two domestic cats with confirmed infection with SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19). These are the first reported companion animals (including pets and service animals) with SARS-CoV-2 infection in the United States, and among the first findings of SARS-CoV-2 symptomatic companion animals reported worldwide. These feline cases originated from separate households and were epidemiologically linked to suspected or confirmed human COVID-19 cases in their respective households. Notification of presumptive positive animal test results triggered a One Health* investigation by state and federal partners, who determined that no further transmission events to other animals or persons had occurred. Both cats fully recovered. Although there is currently no evidence that animals play a substantial role in spreading COVID-19, CDC advises persons with suspected or confirmed COVID-19 to restrict contact with animals during their illness and to monitor any animals with confirmed SARS-CoV-2 infection and separate them from other persons and animals at home (1).

Clonally expanding smooth muscle cells promote atherosclerosis by escaping efferocytosis and activating the complement cascade.

Atherosclerosis is the process underlying heart attack and stroke. Despite decades of research, its pathogenesis remains unclear. Dogma suggests that atherosclerotic plaques expand primarily via the accumulation of cholesterol and inflammatory cells. However, recent evidence suggests that a substantial portion of the plaque may arise from a subset of "dedifferentiated" vascular smooth muscle cells (SMCs) which proliferate in a clonal fashion. Herein we use multicolor lineage-tracing models to confirm that the mature SMC can give rise to a hyperproliferative cell which appears to promote inflammation via elaboration of complement-dependent anaphylatoxins. Despite being extensively opsonized with prophagocytic complement fragments, we find that this cell also escapes immune surveillance by neighboring macrophages, thereby exacerbating its relative survival advantage. Mechanistic studies indicate this phenomenon results from a generalized opsonin-sensing defect acquired by macrophages during polarization. This defect coincides with the noncanonical up-regulation of so-called don't eat me molecules on inflamed phagocytes, which reduces their capacity for programmed cell removal (PrCR). Knockdown or knockout of the key antiphagocytic molecule CD47 restores the ability of macrophages to sense and clear opsonized targets in vitro, allowing for potent and targeted suppression of clonal SMC expansion in the plaque in vivo. Because integrated clinical and genomic analyses indicate that similar pathways are active in humans with cardiovascular disease, these studies suggest that the clonally expanding SMC may represent a translational target for treating atherosclerosis.