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Fetal Neuropathology in Zika Virus-Infected Pregnant Female Rhesus Monkeys

Cell.

2018 Mar 28

Martinot AJ, Abbink P, Afacan O, Prohl AK, Bronson R, Hecht JL, Borducchi EN, Larocca RA, Peterson RL, Rinaldi W, Ferguson M, Didier PJ, Weiss D, Lewis MG, De La Barrera RA, Yang E, Warfield SK, Barouch DH.
PMID: 29606355 | DOI: 10.1016/j.cell.2018.03.019

The development of interventions to prevent congenital Zika syndrome (CZS) has been limited by the lack of an established nonhuman primate model. Here we show that infection of female rhesus monkeys early in pregnancy with Zika virus (ZIKV) recapitulates many features of CZS in humans. We infected 9 pregnant monkeys with ZIKV, 6 early in pregnancy (weeks 6-7 of gestation) and 3 later in pregnancy (weeks 12-14 of gestation), and compared findings with uninfected controls. 100% (6 of 6) of monkeys infected early in pregnancy exhibited prolonged maternal viremia and fetal neuropathology, including fetal loss, smaller brain size, and histopathologic brain lesions, including microcalcifications, hemorrhage, necrosis, vasculitis, gliosis, and apoptosis of neuroprogenitor cells. High-resolution MRI demonstrated concordant lesions indicative of deep gray matter injury. We also observed spinal, ocular, and neuromuscular pathology. Our data show that vascular compromise and neuroprogenitor cell dysfunction are hallmarks of CZS pathogenesis, suggesting novel strategies to prevent and to treat this disease.

Clinicopathological features of squamous cell carcinoma of the oral cavity and oropharynx in young patients

Br J Oral Maxillofac Surg.

2018 Apr 05

Martinez RCP, Sathasivam HP, Cosway B, Paleri V, Fellows S, Adams J, Kennedy M, Pearson R, Long A, Sloan P, Robinson M.
PMID: 29628167 | DOI: 10.1016/j.bjoms.2018.03.011

Our aim was to examine the clinicopathological features of squamous cell carcinoma (SCC) of the oral cavity and oropharynx in a group of young patients who were dignosed during a 15-year period (2000-2014). Patients' clinical details, risk factors, and survival were obtained from medical records. Formalin-fixed, paraffin-embedded, tissue was tested for high-risk human papillomavirus (HPV). The results were compared with those of a matching group of older patients. We identified 91 patients who were younger than 45 years old, and the 50 youngest patients were studied in detail. The male:female ratio was 2:1, with more tumours located in the oral cavity than in the oropharynx (35 compared with 15). HPV-related SCC was restricted to the oropharynx. When matched for site, stage and HPV status, five-year overall survival was similar in young and matched older patients (log-rank test, p=0.515). Our findings suggest that young patients with oral SCC have a disease profile similar to that of older patients with the condition. It is plausible that prognostic information generally available for oral cancers is applicable to young patients with the disease.

Genetic conservation of Cytauxzoon felis antigens and mRNA expression in the schizont life-stage

Veterinary Parasitology

2018 Oct 09

Khana DB, Peterson DS, Stanton JB, Schreeg ME, Birkenheuer AJ, Tarigo JL.
PMID: - | DOI: 10.1016/j.vetpar.2018.10.007

Abstract Cytauxzoonosis is a highly fatal disease of domestic cats caused by the apicomplexan protozoan Cytauxzoon felis, which is most closely related to Theileria spp. The growing prevalence, high morbidity and mortality, and treatment cost of cytauxzoonosis emphasize the need for vaccine development. Traditional approaches for vaccine development, however, have been hindered by the inability to culture C. felis in vitro. Recent availability of the annotated C. felis genome combined with genome-based vaccine design and protein microarray immunoscreening allowed for high-throughput identification of C. felis antigens that could serve as vaccine candidates. This study assessed the suitability of three of these vaccine candidates (cf30, cf63, cf58) in addition to a previously reported vaccine candidate (cf76) based on two criteria: genetic conservation among diverse C. felis geographic isolates and expression in tissues containing the C. felis schizont life stage, which has been previously associated with the development of a protective immune response. A comparison of seventeen C. felis isolates across seven states demonstrated high sequence identity (99-100%) for cf30, cf63, and cf58, similar to the degree of conservation previously reported for cf76. RNAscope™ in situ hybridization using acutely infected feline splenic tissue revealed robust levels of all transcripts in the schizont life stage of the parasite. These data support the suitability of these three antigens for further investigation as vaccine candidates against cytauxzoonosis.

Persistence of Lassa Virus Associated With Severe Systemic Arteritis in Convalescing Guinea Pigs (Cavia porcellus).

J Infect Dis. 2018 Dec 5.

2018 Dec 05

Liu DX, Perry DL, Evans DeWald L, Cai Y, Hagen KR, Cooper TK, Huzella LM, Hart R, Bonilla A, Bernbaum JG, Janosko KB, Adams R, Johnson RF, Kuhn JH, Schnell MJ, Crozier I, Jahrling PB, de la Torre JC.
PMID: 30517671 | DOI: 10.1093/infdis/jiy641

Lassa fever (LF) survivors develop various clinical manifestations including polyserositis, myalgia, epididymitis, and hearing loss weeks to months after recovery from acute infection. We demonstrate a systemic lymphoplasmacytic and histiocytic arteritis and periarteritis in guinea pigs more than 2 months after recovery from acute Lassa virus (LASV) infection. LASV was detected in the arterial tunica media smooth muscle cells by immunohistochemistry, in situ hybridization, and transmission electron microscopy. Our results suggest that the sequelae of LASV infection may be due to virus persistence resulting in systemic vascular damage. These findings shed light on the pathogenesis of LASV sequelae in convalescent human survivors.
Human Papillomavirus-Related Head and Neck Squamous Cell Carcinoma Variants

Seminars in Diagnostic Pathology

Samir K. El-Mofty
PMID: 10.1053/j.semdp.2015.02.022

During the last few decades a phenotypically distinct type of head and neck squamous cell carcinoma (SCC), that is etiologically related to human papillomavirus(HPV), has emerged and its prevalence continues to increase. The tumors are site-specific with special predilection for the oropharynx. They are morphologically and molecularly distinct and are responsive to different types of treatment modalities, with excellent clinical outcome, in spite of early lymph node metastasis. Microscopically, the carcinomas are nonkeratinizing SCCs. More recently, other variants that are believed to be etiologically related to HPV are reported. As a result, several clinical and pathologic questions have emerged. Importantly, whether the virus is biologically active in these tumors and involved in their pathogenesis, and second, what are the clinical implications with regard to patient management and outcome in these HPV-related variants. This review is an attempt to answer some of these questions based on information derived from available yet limited number of publications. The variants to be discussed include; nonkeratinizing SCC (NKSCC), NKSCC with maturation (hybrid type), keratinizing SCC (KSSC), basaloid squamous carcinoma (BSCC), undifferentiated carcinoma (UC), papillary SCC (PSCC), small cell carcinoma, adenosquamous carcinoma (AdSCC) and spindle cell (sarcomatoid) carcinoma.
HPV-related oropharyngeal squamous cell carcinomas: a comparison between three diagnostic approaches.

Am J Otolaryngol. 2014 Jan-Feb;35(1):25-32.

Melkane AE, Mirghani H, Aupérin A, Saulnier P, Lacroix L, Vielh P, Casiraghi O, Griscelli F, Temam S.
PMID: 24112760 | DOI: 10.1016/j.amjoto.2013.08.007.

PURPOSE: HPV-related oropharyngeal squamous cell carcinomas clearly represent a growing entity in the head and neck with distinct carcinogenesis, clinico-pathological presentation and survival profile. We aimed to compare the HPV prevalence rates and clinico-pathological correlations obtained with three distinct commonly used HPV detection methods. MATERIALS AND METHODS: p16-immunohistochemistry (IHC), HPV DNA viral load by real-time PCR (qPCR), and HPV genotyping by a reverse hybridization-based line probe assay (INNO-LiPA) were performed on pretreatment formalin-fixed paraffin-embedded tumor samples from 46 patients treated for single primary oropharyngeal carcinomas. RESULTS: Twenty-eight patients (61%) had a p16 overexpression in IHC. Twenty-nine patients (63%) harbored HPV DNA on qPCR. Thirty-four patients (74%) harbored HPV DNA on INNO-LiPA. The concordance analysis revealed a good agreement between both HPV DNA detection methods (κ=0.65); when both tests were positive, the depicted HPV subtypes were always concordant (HPV16 in 27 cases, HPV18 in 1 case). Agreement was moderate between IHC and qPCR (κ=0.59) and fair between IHC and INNO-LiPA (κ=0.22). CONCLUSIONS: Certain highly sensitive methods are able to detect the mere presence of HPV without any carcinogenetic involvement while other more specific tests provide proof of viral transcriptional activity and thus evidence of clinically relevant infections. The use of a stepwise approach allows reducing false positives; p16-immunostaining seems to be an excellent screening test and in situ hybridization may overcome some of the PCR limitations.
Human papillomavirus-related mixed non-keratinizing squamous cell carcinoma of the palatine tonsil with small cell neuroendocrine carcinoma: Report of a case

Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology

2016 Oct 21

Ma Y, Patil N, Gagner JP, Miles BA.
PMID: - | DOI: 10.1016/j.ajoms.2016.09.010

Increased testing for human papillomavirus (HPV) in oropharyngeal carcinomas has broadened the range of HPV-associated malignancies identified at this site. While HPV-related oropharyngeal non-keratinizing squamous cell carcinomas (SCC) are known to have a better prognosis than their non-HPV counterparts, HPV positivity may not alter the aggressive nature of HPV-associated small cell neuroendocrine carcinomas (SCNEC). We report a unique case of a mixed non-keratinizing type HPV-associated tonsillar SCC with SCNEC differentiation, and provide a comparison with the rare reported cases of such mixed carcinomas in the literature. Our patient is only the second such case positive for HPV genotype 18 and the only case in which this HPV-related mixed tonsillar tumor occurred in a patient with small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL). The case discussion supports the concept that HPV positivity does not confer a better prognosis in such mixed non-keratinizing type SCC with SCNEC. Our report also alerts pathologists to the need to evaluate for the possibility of a coexisting neuroendocrine component when oropharyngeal squamous cell carcinoma (OPSCC) is diagnosed, as its presence will affect the patients’ clinical management and prognosis

WNT ligands control initiation and progression of human papillomavirus-driven squamous cell carcinoma

Oncogene.

2018 Apr 17

Zimmerli D, Cecconi V, Valenta T, Hausmann G, Cantù C, Restivo G, Hafner J, Basler K, van den Broek M.
PMID: 29662191 | DOI: 10.1038/s41388-018-0244-x

Human papillomavirus (HPV)-driven cutaneous squamous cell carcinoma (cSCC) is the most common cancer in immunosuppressed patients. Despite indications suggesting that HPV promotes genomic instability during cSCC development, the molecular pathways underpinning HPV-driven cSCC development remain unknown. We compared the transcriptome of HPV-driven mouse cSCC with normal skin and observed higher amounts of transcripts for Porcupine and WNT ligands in cSCC, suggesting a role for WNT signaling in cSCC progression. We confirmed increased Porcupine expression in human cSCC samples. Blocking the secretion of WNT ligands by the Porcupine inhibitor LGK974 significantly diminished initiation and progression of HPV-driven cSCC. Administration of LGK974 to mice with established cSCC resulted in differentiation of cancer cells and significant reduction of the cancer stem cell compartment. Thus, WNT/β-catenin signaling is essential for HPV-driven cSCC initiation and progression as well as for maintaining the cancer stem cell niche. Interference with WNT secretion may thus represent a promising approach for therapeutic intervention.

A novel role for C–C motif chemokine receptor 2 during infection with hypervirulent Mycobacterium tuberculosis

Mucosal Immunol.

2018 Aug 16

Dunlap MD, Howard N, Das S, Scott N, Ahmed M, Prince O, Rangel-Moreno J, Rosa BA, Martin J, Kaushal D, Kaplan G, Mitreva M, Kim KW, Randolph GJ, Khader SA.
PMID: 30115997 | DOI: 10.1038/s41385-018-0071-y

C-C motif chemokine receptor 2 (CCR2) is a major chemokine axis that recruits myeloid cells including monocytes and macrophages. Thus far, CCR2-/- mice have not been found to be susceptible to infection with Mycobacterium tuberculosis (Mtb). Here, using a prototype W-Beijing family lineage 2 Mtb strain, HN878, we show that CCR2-/- mice exhibit increased susceptibility to tuberculosis (TB). Following exposure to Mtb HN878, alveolar macrophages (AMs) are amongst the earliest cells infected. We show that AMs accumulate early in the airways following infection and express CCR2. During disease progression, CCR2-expressing AMs exit the airways and localize within the TB granulomas. RNA-sequencing of sorted airway and non-airway AMs from infected mice show distinct gene expression profiles, suggesting that upon exit from airways and localization within granulomas, AMs become classically activated. The absence of CCR2+ cells specifically at the time of AM egress from the airways resulted in enhanced susceptibility to Mtb infection. Furthermore, infection with an Mtb HN878 mutant lacking phenolic glycolipid (PGL) expression still resulted in increased susceptibility in CCR2-/- mice. Together, these data show a novel rolefor CCR2 in protective immunity against clinically relevant Mtb infections.

Interferon lambda protects the female reproductive tract against Zika virus infection.

Nat Commun. 2019 Jan 17;10(1):280.

2019 Jan 17

Caine EA, Scheaffer SM, Arora N, Zaitsev K, Artyomov MN, Coyne CB, Moley KH, Diamond MS.
PMID: PMID: 30655513 | DOI: DOI:10.1038/s41467-018-07993-2

Although Zika virus (ZIKV) can be transmitted sexually and cause congenital birth defects, immune control mechanisms in the female reproductive tract (FRT) are not well characterized. Here we show that treatment of primary human vaginal and cervical epithelial cells with interferon (IFN)-α/β or IFN-λ induces host defense transcriptional signatures and inhibits ZIKV infection. We also assess the effects of IFNs on intravaginal infection of the FRT using ovariectomized mice treated with reproductive hormones. We find that mice receiving estradiol are protected against intravaginal ZIKV infection, independently of IFN-α/β or IFN-λ signaling. In contrast, mice lacking IFN-λ signaling sustain greater FRT infection when progesterone is administered. Exogenous IFN-λ treatment confers an antiviral effect when mice receive both estradiol and progesterone, but not progesterone alone. Our results identify a hormonal stage-dependent role for IFN-λ in controlling ZIKV infection in the FRT and suggest a path for minimizing sexual transmission of ZIKV in women.
ARID1A loss derepresses a group of human endogenous retrovirus-H loci to modulate BRD4-dependent transcription

Nature communications

2022 Jun 17

Yu, C;Lei, X;Chen, F;Mao, S;Lv, L;Liu, H;Hu, X;Wang, R;Shen, L;Zhang, N;Meng, Y;Shen, Y;Chen, J;Li, P;Huang, S;Lin, C;Zhang, Z;Yuan, K;
PMID: 35715442 | DOI: 10.1038/s41467-022-31197-4

Transposable elements (TEs) through evolutionary exaptation have become an integral part of the human genome, offering ample regulatory sequences and shaping chromatin 3D architecture. While the functional impacts of TE-derived sequences on early embryogenesis have been recognized, their roles in malignancy are only starting to emerge. Here we show that many TEs, especially the pluripotency-related human endogenous retrovirus H (HERVH), are abnormally activated in colorectal cancer (CRC) samples. Transcriptional upregulation of HERVH is associated with mutations of several tumor suppressors, particularly ARID1A. Knockout of ARID1A in CRC cells leads to increased transcription at several HERVH loci, which involves compensatory contribution by ARID1B. Suppression of HERVH in CRC cells and patient-derived organoids impairs tumor growth. Mechanistically, HERVH transcripts colocalize with nuclear BRD4 foci, modulating their dynamics and co-regulating many target genes. Altogether, we uncover a critical role for ARID1A in restraining HERVH, whose abnormal activation can promote tumorigenesis by stimulating BRD4-dependent transcription.
Long-term hepatitis B virus infection of rhesus macaques requires suppression of host immunity

Nature communications

2022 May 30

Biswas, S;Rust, LN;Wettengel, JM;Yusova, S;Fischer, M;Carson, JN;Johnson, J;Wei, L;Thode, T;Kaadige, MR;Sharma, S;Agbaria, M;Bimber, BN;Tu, T;Protzer, U;Ploss, A;Smedley, JV;Golomb, G;Sacha, JB;Burwitz, BJ;
PMID: 35637225 | DOI: 10.1038/s41467-022-30593-0

Hepatitis B virus has infected a third of the world's population, and 296 million people are living with chronic infection. Chronic infection leads to progressive liver disease, including hepatocellular carcinoma and liver failure, and there remains no reliable curative therapy. These gaps in our understanding are due, in large part, to a paucity of animal models of HBV infection. Here, we show that rhesus macaques regularly clear acute HBV infection, similar to adult humans, but can develop long-term infection if immunosuppressed. Similar to patients, we longitudinally detected HBV DNA, HBV surface antigen, and HBV e antigen in the serum of experimentally infected animals. In addition, we discovered hallmarks of HBV infection in the liver, including RNA transcription, HBV core and HBV surface antigen translation, and covalently closed circular DNA biogenesis. This pre-clinical animal model will serve to accelerate emerging HBV curative therapies into the clinic.

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Description
sense
Example: Hs-LAG3-sense
Standard probes for RNA detection are in antisense. Sense probe is reverse complent to the corresponding antisense probe.
Intron#
Example: Mm-Htt-intron2
Probe targets the indicated intron in the target gene, commonly used for pre-mRNA detection
Pool/Pan
Example: Hs-CD3-pool (Hs-CD3D, Hs-CD3E, Hs-CD3G)
A mixture of multiple probe sets targeting multiple genes or transcripts
No-XSp
Example: Hs-PDGFB-No-XMm
Does not cross detect with the species (Sp)
XSp
Example: Rn-Pde9a-XMm
designed to cross detect with the species (Sp)
O#
Example: Mm-Islr-O1
Alternative design targeting different regions of the same transcript or isoforms
CDS
Example: Hs-SLC31A-CDS
Probe targets the protein-coding sequence only
EnEmProbe targets exons n and m
En-EmProbe targets region from exon n to exon m
Retired Nomenclature
tvn
Example: Hs-LEPR-tv1
Designed to target transcript variant n
ORF
Example: Hs-ACVRL1-ORF
Probe targets open reading frame
UTR
Example: Hs-HTT-UTR-C3
Probe targets the untranslated region (non-protein-coding region) only
5UTR
Example: Hs-GNRHR-5UTR
Probe targets the 5' untranslated region only
3UTR
Example: Rn-Npy1r-3UTR
Probe targets the 3' untranslated region only
Pan
Example: Pool
A mixture of multiple probe sets targeting multiple genes or transcripts

Enabling research, drug development (CDx) and diagnostics

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