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Article: The effect of molnupiravir and nirmatrelvir on SARS-CoV-2 genome diversity in infected and immune suppressed mice.

Penrice-Randal, Rebekah / Bentley, Eleanor G / Sharma, Parul / Kirby, Adam / Donovan-Banfield, I'ah / Kipar, Anja / Mega, Daniele F / Bramwell, Chloe / Sharp, Joanne / Owen, Andrew / Hiscox, Julian A / Stewart, James P

bioRxiv : the preprint server for biology

2024

Abstract: Objectives: Immunocompromised individuals are susceptible to severe COVID-19 and potentially contribute to the emergence of variants with altered pathogenicity due to persistent infection. This study investigated the impact of immunosuppression on SARS- ... ...

Abstract	Objectives: Immunocompromised individuals are susceptible to severe COVID-19 and potentially contribute to the emergence of variants with altered pathogenicity due to persistent infection. This study investigated the impact of immunosuppression on SARS-CoV-2 infection in k18-hACE2 mice and the effectiveness of antiviral treatments in this context. Methods: Mice were immunosuppressed using cyclophosphamide and infected with a B lineage of SARS-CoV-2. Molnupiravir and nirmatrelvir, alone and in combination, were administered and viral load and viral sequence diversity was assessed. Results: Treatment of infected but immune compromised mice with both compounds either singly or in combination resulted in decreased viral loads and pathological changes compared to untreated animals. Treatment also abrogated infection of neuronal tissue. However, no consistent changes in the viral consensus sequence were observed, except for the emergence of the S:H655Y mutation. Molnupiravir, but not nirmatrelvir or immunosuppression alone, increased the transition/transversion (Ts/Tv) ratio, representative of A>G and C>U mutations and this increase was not altered by the co-administration of nirmatrelvir with molnupiravir.Notably, immunosuppression itself did not appear to promote the emergence of mutational characteristic of variants of concern (VOCs). Conclusions: Further investigations are warranted to fully understand the role of immunocompromised individuals in VOC development and to inform optimised public health strategies. It is more likely that immunodeficiency promotes viral persistence but does not necessarily lead to substantial consensus-level changes in the absence of antiviral selection pressure. Consistent with mechanisms of action, molnupiravir showed a stronger mutagenic effect than nirmatrelvir in this model.
Language	English
Publishing date	2024-02-28
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.02.27.582110
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Article ; Online: The effect of molnupiravir and nirmatrelvir on SARS-CoV-2 genome diversity in infected and immune suppressed mice

bioRxiv

Abstract	Objectives: Immunocompromised individuals are susceptible to severe COVID-19 and potentially contribute to the emergence of variants with altered pathogenicity due to persistent infection. This study investigated the impact of immunosuppression on SARS-CoV-2 infection in k18-hACE2 mice and the effectiveness of antiviral treatments in this context. Methods: Mice were immunosuppressed using cyclophosphamide and infected with a B lineage of SARS-CoV-2. Molnupiravir and nirmatrelvir, alone and in combination, were administered and viral load and viral sequence diversity was assessed. Results: Treatment of infected but immune compromised mice with both compounds either singly or in combination resulted in decreased viral loads and pathological changes compared to untreated animals. Treatment also abrogated infection of neuronal tissue. However, no consistent changes in the viral consensus sequence were observed, except for the emergence of the S:H655Y mutation. Molnupiravir, but not nirmatrelvir or immunosuppression alone, increased the transition/transversion (Ts/Tv) ratio, indicative of A>G and C>U mutations. Notably, immunosuppression itself did not appear to promote the emergence of mutations characteristic of variants of concern (VOCs). Conclusions: Further investigations are warranted to fully understand the role of immunocompromised individuals in VOC development and to inform optimised public health strategies. It is more likely that immunodeficiency promotes viral persistence but does not necessarily lead to substantial consensus-level changes in the absence of antiviral selection pressure. Molnupiravir, compared to nirmatrelvir, shows a stronger mutagenic effect in this model.
Keywords	covid19
Language	English
Publishing date	2024-02-28
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2024.02.27.582110
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Article ; Online: Chemoprophylactic Assessment of Combined Intranasal SARS-CoV-2 Polymerase and Exonuclease Inhibition in Syrian Golden Hamsters.

Gallardo-Toledo, Eduardo / Neary, Megan / Sharp, Joanne / Herriott, Joanne / Kijak, Edyta / Bramwell, Chloe / Curley, Paul / Arshad, Usman / Pertinez, Henry / Rajoli, Rajith K R / Valentijn, Anthony / Cox, Helen / Tatham, Lee / Kipar, Anja / Stewart, James P / Owen, Andrew

Viruses

2023 Volume 15, Issue 11

Abstract: Pibrentasvir (PIB) has been demonstrated to block exonuclease activity of the SARS-CoV-2 polymerase, protecting favipiravir (FVP) and remdesivir (RDV) from post-incorporation excision and eliciting antiviral synergy in vitro. The present study ... ...

Abstract	Pibrentasvir (PIB) has been demonstrated to block exonuclease activity of the SARS-CoV-2 polymerase, protecting favipiravir (FVP) and remdesivir (RDV) from post-incorporation excision and eliciting antiviral synergy in vitro. The present study investigated the chemoprophylactic efficacy of PIB, FVP, RDV, FVP with PIB, or RDV with PIB dosed intranasally twice a day, using a Syrian golden hamster contact transmission model. Compared to the saline control, viral RNA levels were significantly lower in throat swabs in FVP (day 7), RDV (day 3, 5, 7), and RDV+PIB (day 3, 5) treatment groups. Similarly, findings were evident for nasal turbinate after PIB and RDV treatment, and lungs after PIB, FVP, and FVP+PIB treatment at day 7. Lung viral RNA levels after RDV and RDV+PIB treatment were only detectable in two animals per group, but the overall difference was not statistically significant. In situ examination of the lungs confirmed SARS-CoV-2 infection in all animals, except for one in each of the RDV and RDV+PIB treatment groups, which tested negative in all virus detection approaches. Overall, prevention of transmission was observed in most animals treated with RDV, while other agents reduced the viral load following contact transmission. No benefit of combining FVP or RDV with PIB was observed.
MeSH term(s)	Cricetinae ; Animals ; SARS-CoV-2 ; Mesocricetus ; COVID-19/prevention & control ; Lung ; Nucleotidyltransferases ; RNA, Viral ; Antiviral Agents/pharmacology ; Antiviral Agents/therapeutic use
Chemical Substances	Nucleotidyltransferases (EC 2.7.7.-) ; RNA, Viral ; Antiviral Agents
Language	English
Publishing date	2023-10-27
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v15112161
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Article ; Online: Evaluation of Nafamostat as Chemoprophylaxis for SARS-CoV-2 Infection in Hamsters.

Viruses

2023 Volume 15, Issue 8

Abstract: The successful development of a chemoprophylaxis against SARS-CoV-2 could provide a tool for infection prevention that is implementable alongside vaccination programmes. Nafamostat is a serine protease inhibitor that inhibits SARS-CoV-2 entry in vitro, ... ...

Abstract	The successful development of a chemoprophylaxis against SARS-CoV-2 could provide a tool for infection prevention that is implementable alongside vaccination programmes. Nafamostat is a serine protease inhibitor that inhibits SARS-CoV-2 entry in vitro, but it has not been characterised for chemoprophylaxis in animal models. Clinically, nafamostat is limited to intravenous delivery and has an extremely short plasma half-life. This study sought to determine whether intranasal dosing of nafamostat at 5 mg/kg twice daily was able to prevent the airborne transmission of SARS-CoV-2 from infected to uninfected Syrian Golden hamsters. SARS-CoV-2 RNA was detectable in the throat swabs of the water-treated control group 4 days after cohabitation with a SARS-CoV-2 inoculated hamster. However, throat swabs from the intranasal nafamostat-treated hamsters remained SARS-CoV-2 RNA negative for the full 4 days of cohabitation. Significantly lower SARS-CoV-2 RNA concentrations were seen in the nasal turbinates of the nafamostat-treated group compared to the control (
MeSH term(s)	Animals ; Cricetinae ; COVID-19/prevention & control ; SARS-CoV-2 ; RNA, Viral ; Chemoprevention ; Mesocricetus
Chemical Substances	nafamostat (Y25LQ0H97D) ; RNA, Viral
Language	English
Publishing date	2023-08-15
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v15081744
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Article ; Online: Acute surgical unit improves outcomes in appendicectomy.

Kinnear, Ned / Bramwell, Eliza / Frazzetto, Alannah / Noll, Amy / Patel, Prajay / Hennessey, Derek / Otto, Greg / Dobbins, Christopher / Sammour, Tarik / Moore, James

ANZ journal of surgery

2019 Volume 89, Issue 9, Page(s) 1108–1113

Abstract: ... patients had similar length of stay (1.81 versus 1.81 days; P = 0.54) and time to theatre (0.59 versus 0.56 ... days; P = 0.14), but a greater proportion of in-hours operation (72% versus 79%; P = 0.014). The ASU ... group also experienced fewer complications (9% versus 6%; P = 0.031), fewer primary open (4% versus 1 ...

Abstract	Background: Few large Australian studies have explored the impact of acute surgical unit (ASU) model in appendicitis. Methods: An ASU model commenced practice at our institution on 1 August 2012. In this retrospective cohort study, patients undergoing appendicectomy 2.5 years before (Traditional group) or after (ASU group) this date were compared. Primary outcomes were median length of stay, median time from emergency department referral to theatre start and proportion of cases performed in-hours. Secondary outcomes were rates of complications, open appendicectomy, consultant scrubbed for procedure, intensive care unit admission and re-presentation to emergency department within 30 days. Results: After removing those with incomplete data, 1214 patients were enrolled; 465 in the Traditional group and 749 in the ASU group. There were no significant baseline differences between groups. Compared with the Traditional group, ASU patients had similar length of stay (1.81 versus 1.81 days; P = 0.54) and time to theatre (0.59 versus 0.56 days; P = 0.14), but a greater proportion of in-hours operation (72% versus 79%; P = 0.014). The ASU group also experienced fewer complications (9% versus 6%; P = 0.031), fewer primary open (4% versus 1%; P < 0.0001) or conversion-to-open appendicectomies (6% versus 2%; P < 0.0005) and had superior rates of consultant scrubbed in theatre (21% versus 56%; P < 0.00001). Rates of intensive care unit admission (1% versus 1%; P = 0.72) and re-presentation were unchanged (5% versus 5%; P = 0.46). Conclusion: In our institution, the introduction of an ASU model was associated with more in-hours operations and safer care for patients undergoing appendicectomy.
MeSH term(s)	Adult ; Appendectomy ; Appendicitis/surgery ; Cohort Studies ; Emergency Service, Hospital ; Female ; Humans ; Male ; Retrospective Studies ; Surgery Department, Hospital ; Treatment Outcome ; Young Adult
Language	English
Publishing date	2019-04-15
Publishing country	Australia
Document type	Journal Article
ZDB-ID	2050749-5
ISSN	1445-2197 ; 1445-1433 ; 0004-8682
ISSN (online)	1445-2197
ISSN	1445-1433 ; 0004-8682
DOI	10.1111/ans.15141
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Article ; Online: Communication and management of incidental pathology in 1,214 consecutive appendicectomies; a cohort study.

Kinnear, Ned / Heijkoop, Bridget / Bramwell, Eliza / Frazzetto, Alannah / Noll, Amy / Patel, Prajay / Hennessey, Derek / Otto, Greg / Dobbins, Christopher / Sammour, Tarik / Moore, James

International journal of surgery (London, England)

2019 Volume 72, Page(s) 185–191

Abstract: ... with regards to communication of the findings to the patient (p = 0.44) and their GP (p = 0.27), and there was ... no difference in the rates of appropriate management (p = 0.21).: Conclusion: The introduction ...

Abstract	Background: Important incidental pathology requiring further action is commonly found during appendicectomy, macro- and microscopically. We aimed to determine whether the acute surgical unit (ASU) model improved the management and disclosure of these findings. Methods: An ASU model was introduced at our institution on 01/08/2012. In this retrospective cohort study, all patients undergoing appendicectomy 2.5 years before (Traditional group) or after (ASU group) this date were compared. The primary outcomes were rates of appropriate management of the incidental findings, and communication of the findings to the patient and to their general practitioner (GP). Results: 1,214 patients underwent emergency appendicectomy; 465 in the Traditional group and 749 in the ASU group. 80 (6.6%) patients (25 and 55 in each respective period) had important incidental findings. There were 24 patients with benign polyps, 15 with neuro-endocrine tumour, 11 with endometriosis, 8 with pelvic inflammatory disease, 8 Enterobius vermicularis infection, 7 with low grade mucinous cystadenoma, 3 with inflammatory bowel disease, 2 with diverticulitis, 2 with tubo-ovarian mass, 1 with secondary appendiceal malignancy and none with primary appendiceal adenocarcinoma. One patient had dual pathologies. There was no difference between the Traditional and ASU group with regards to communication of the findings to the patient (p = 0.44) and their GP (p = 0.27), and there was no difference in the rates of appropriate management (p = 0.21). Conclusion: The introduction of an ASU model did not change rates of surgeon-to-patient and surgeon-to-GP communication nor affect rates of appropriate management of important incidental pathology during appendectomy.
MeSH term(s)	Adult ; Appendectomy ; Appendicitis/pathology ; Appendicitis/surgery ; Appendix/pathology ; Communication ; Emergency Service, Hospital ; Female ; Humans ; Male ; Middle Aged ; Retrospective Studies
Language	English
Publishing date	2019-11-02
Publishing country	England
Document type	Journal Article
ZDB-ID	2212038-5
ISSN	1743-9159 ; 1743-9191
ISSN (online)	1743-9159
ISSN	1743-9191
DOI	10.1016/j.ijsu.2019.10.025
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Article ; Online: SARS-CoV-2 Omicron-B.1.1.529 Variant leads to less severe disease than Pango B and Delta variants strains in a mouse model of severe COVID-19

Bentley, Eleanor G / Kirby, Adam / Sharma, Parul / Kipar, Anja / Mega, Daniele F / Bramwell, Chloe / Penrice-Randal, Rebekah / Prince, Tessa / Brown, Jonathan C / Zhou, Jie / Screaton, Gavin R / Barclay, Wendy S / Owen, Andrew / Hiscox, Julian Alexander / Stewart, James P

bioRxiv

Abstract: COVID-19 is a spectrum of clinical symptoms in humans caused by infection with SARS-CoV-2. The B.1.1.529 Omicron variant is rapidly emerging and has been designated a Variant of Concern (VOC). The variant is highly transmissible and partially or fully ... ...

Abstract	COVID-19 is a spectrum of clinical symptoms in humans caused by infection with SARS-CoV-2. The B.1.1.529 Omicron variant is rapidly emerging and has been designated a Variant of Concern (VOC). The variant is highly transmissible and partially or fully evades a spectrum of neutralising antibodies due to a high number of substitutions in the spike glycoprotein. A major question is the relative severity of disease caused by the Omicron variant compared with previous and currently circulating variants of SARS-CoV-2. To address this, a mouse model of infection that recapitulates severe disease in humans, K18-hACE2 mice, were infected with either a Pango B, Delta or Omicron variant of SARS-CoV-2 and their relative pathogenesis compared. In contrast to mice infected with Pango B and Delta variant viruses, those infected with the Omicron variant had less severe clinical signs (weight loss), showed recovery and had a lower virus load in both the lower and upper respiratory tract. This is also reflected by less extensive inflammatory processes in the lungs. Although T cell epitopes may be conserved, the antigenic diversity of Omicron from previous variants would suggest that a change in vaccine may be required to mitigate against the higher transmissibility and global disease burden. However, the lead time to develop such a response may be too late to mitigate the spread and effects of Omicron. These animal model data suggest the clinical consequences of infection with the Omicron variant may be less severe but the higher transmissibility could still place huge burden upon healthcare systems even if a lower proportion of infected patients are hospitalised.
Keywords	covid19
Language	English
Publishing date	2021-12-28
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2021.12.26.474085
Database	COVID19

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Article ; Online: Successful expanded clinic network collaboration and patient tracing for retention in HIV care.

Bhatt, Shivani / Bryant, Mellissa / Lau, Helen / Tee, Ban-Kiem / Eu, Beng / O'Bryan, Jessica / Woolley, Ian / Mitchell, Jeni / Street, Alan / Dobinson, Sheranne / Medland, Nicholas / Lamb, Judy / Mahony, Andrew / Tramontana, Adrian / Lim, Lyn-Li / Wade, Amanda / Roder, Christine / Mitchell, William / Sherman, Christopher /

Bramwell, Fran / Aboltins, Craig / Wong, Siaw Hui / Giourouki, Maxine / Hoy, Jennifer F / McMahon, James H

AIDS research and therapy

2022 Volume 19, Issue 1, Page(s) 61

Abstract: ... who identify as heterosexual or unknown) (74.5% vs. 53.5%, [p = 0.06]) and receiving ART at their last HIV-care ... visit (84.3% vs. 67.8% [p = 0.09]).: Conclusion: This study confirmed high retention in HIV-care and ...

Abstract	Background: There are more than 7,800 people living with human immunodeficiency virus (HIV) in Victoria, Australia. Crucial in maximising the individual and population level benefits from antiretroviral therapy (ART) is understanding how to achieve patient retention in care and the factors that drive it. This study was an expansion of a 2015 assessment of HIV-care retention in Victoria, which sought out to determine whether the inclusion of a broader range of HIV-healthcare sites would yield more accurate estimates of retention in HIV-care. We aimed to improve our understanding of HIV-care retention in Victoria, Australia, identify people living with HIV (PLHIV) with unknown outcomes, and attempt to re-engage PLHIV in care. Methods: A network of 15 HIV-care sites was established in Victoria, Australia across diverse care settings which ranged from low-caseload rural sites to high-caseload metropolitan GP clinics and hospitals. Individuals who had an HIV viral load (VL) performed in both calendar years of 2016 and 2017 were classified as retained in care. Individuals with a VL test in 2016 but not in 2017 were considered to potentially have unknown outcomes as they may have been receiving care elsewhere, have disengaged from care or died. For this group, an intervention of cross-referencing partially de-identified data between healthcare sites, and contact tracing individuals who still had unknown outcomes was performed. Results: For 5223 individuals considered to be retained in care across 15 healthcare sites in the study period, 49 had unconfirmed transfers of care to an alternative provider and 79 had unknown outcomes. After the intervention, the number of unconfirmed care transfers was reduced to 17 and unknown outcomes reduced to 51. These changes were largely attributed to people being reclassified as confirmed transfers of care. Retention in care estimates that did not include the patient outcome of confirmed transfer of care ranged from 76.2 to 95.8% and did not alter with the intervention. However, retention in care estimates which considered confirmed transfers and those that re-entered care at a new site as retained in care significantly increased across five of the sites with estimates ranging from 80.9 to 98.3% pre-intervention to 83.3-100% post-intervention. Individuals whose outcomes remained unknown post-intervention were more often men who have sex with men (MSM) when compared to other categories (person who injects drugs (PWID), combined PWID/MSM, men who identify as heterosexual or unknown) (74.5% vs. 53.5%, [p = 0.06]) and receiving ART at their last HIV-care visit (84.3% vs. 67.8% [p = 0.09]). Conclusion: This study confirmed high retention in HIV-care and low numbers of people disengaged from HIV-care in Victoria. This was demonstrated across a larger number of sites with varying models of care than a prior assessment in 2015. These data align with national and state targets aiming for 95% of PLHIV retained in HIV-care.
MeSH term(s)	Male ; Humans ; HIV Infections/drug therapy ; HIV Infections/epidemiology ; Homosexuality, Male ; Substance Abuse, Intravenous ; Sexual and Gender Minorities ; Retention in Care
Language	English
Publishing date	2022-12-05
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2173450-1
ISSN	1742-6405 ; 1742-6405
ISSN (online)	1742-6405
ISSN	1742-6405
DOI	10.1186/s12981-022-00476-x
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Article ; Online: FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2.

Brevini, Teresa / Maes, Mailis / Webb, Gwilym J / John, Binu V / Fuchs, Claudia D / Buescher, Gustav / Wang, Lu / Griffiths, Chelsea / Brown, Marnie L / Scott, William E / Pereyra-Gerber, Pehuén / Gelson, William T H / Brown, Stephanie / Dillon, Scott / Muraro, Daniele / Sharp, Jo / Neary, Megan / Box, Helen / Tatham, Lee /

Stewart, James / Curley, Paul / Pertinez, Henry / Forrest, Sally / Mlcochova, Petra / Varankar, Sagar S / Darvish-Damavandi, Mahnaz / Mulcahy, Victoria L / Kuc, Rhoda E / Williams, Thomas L / Heslop, James A / Rossetti, Davide / Tysoe, Olivia C / Galanakis, Vasileios / Vila-Gonzalez, Marta / Crozier, Thomas W M / Bargehr, Johannes / Sinha, Sanjay / Upponi, Sara S / Fear, Corrina / Swift, Lisa / Saeb-Parsy, Kourosh / Davies, Susan E / Wester, Axel / Hagström, Hannes / Melum, Espen / Clements, Darran / Humphreys, Peter / Herriott, Jo / Kijak, Edyta / Cox, Helen / Bramwell, Chloe / Valentijn, Anthony / Illingworth, Christopher J R / Dahman, Bassam / Bastaich, Dustin R / Ferreira, Raphaella D / Marjot, Thomas / Barnes, Eleanor / Moon, Andrew M / Barritt, Alfred S / Gupta, Ravindra K / Baker, Stephen / Davenport, Anthony P / Corbett, Gareth / Gorgoulis, Vassilis G / Buczacki, Simon J A / Lee, Joo-Hyeon / Matheson, Nicholas J / Trauner, Michael / Fisher, Andrew J / Gibbs, Paul / Butler, Andrew J / Watson, Christopher J E / Mells, George F / Dougan, Gordon / Owen, Andrew / Lohse, Ansgar W / Vallier, Ludovic / Sampaziotis, Fotios

Nature

2022 Volume 615, Issue 7950, Page(s) 134–142

Abstract: Preventing SARS-CoV-2 infection by modulating viral host receptors, such as angiotensin-converting enzyme 2 (ACE2) ...

Abstract	Preventing SARS-CoV-2 infection by modulating viral host receptors, such as angiotensin-converting enzyme 2 (ACE2)
MeSH term(s)	Animals ; Humans ; Mice ; Angiotensin-Converting Enzyme 2/genetics ; Angiotensin-Converting Enzyme 2/metabolism ; COVID-19/metabolism ; COVID-19/prevention & control ; Receptors, Virus/genetics ; Receptors, Virus/metabolism ; Retrospective Studies ; SARS-CoV-2/metabolism ; COVID-19 Drug Treatment ; Cricetinae ; Transcription, Genetic ; Ursodeoxycholic Acid/pharmacology ; Lung/drug effects ; Lung/metabolism ; Organoids/drug effects ; Organoids/metabolism ; Liver/drug effects ; Liver/metabolism ; Nasal Mucosa/drug effects ; Nasal Mucosa/metabolism ; Registries ; Reproducibility of Results ; Liver Transplantation
Chemical Substances	Angiotensin-Converting Enzyme 2 (EC 3.4.17.23) ; Receptors, Virus ; ACE2 protein, human (EC 3.4.17.23) ; farnesoid X-activated receptor (0C5V0MRU6P) ; pregna-4,17-diene-3,16-dione (A4PW148END) ; Ursodeoxycholic Acid (724L30Y2QR)
Language	English
Publishing date	2022-12-05
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	120714-3
ISSN	1476-4687 ; 0028-0836
ISSN (online)	1476-4687
ISSN	0028-0836
DOI	10.1038/s41586-022-05594-0
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Article ; Online: Tryptophan hydroxylase Is Required for Eye Melanogenesis in the Planarian Schmidtea mediterranea.

Bramwell G Lambrus / Olivier Cochet-Escartin / Jiarong Gao / Phillip A Newmark / Eva-Maria S Collins / James J Collins

PLoS ONE, Vol 10, Iss 5, p e

2015 Volume 0127074

Abstract: Melanins are ubiquitous and biologically important pigments, yet the molecular mechanisms that regulate their synthesis and biochemical composition are not fully understood. Here we present a study that supports a role for serotonin in melanin synthesis ... ...

Abstract	Melanins are ubiquitous and biologically important pigments, yet the molecular mechanisms that regulate their synthesis and biochemical composition are not fully understood. Here we present a study that supports a role for serotonin in melanin synthesis in the planarian Schmidtea mediterranea. We characterize the tryptophan hydroxylase (tph) gene, which encodes the rate-limiting enzyme in serotonin synthesis, and demonstrate by RNA interference that tph is essential for melanin production in the pigment cups of the planarian photoreceptors. We exploit this phenotype to investigate the biological function of pigment cups using a quantitative light-avoidance behavioral assay. Planarians lacking eye pigment remain phototactic, indicating that eye pigmentation is not essential for light avoidance in S. mediterranea, though it improves the efficiency of the photophobic response. Finally, we show that the eye pigmentation defect observed in tph knockdown animals can be rescued by injection of either the product of TPH, 5-hydroxytryptophan (5-HTP), or serotonin. Together, these results highlight a role for serotonin in melanogenesis, perhaps as a regulatory signal or as a pigment substrate. To our knowledge, this is the first example of this relationship to be reported outside of mammalian systems.
Keywords	Medicine ; R ; Science ; Q
Subject code	570
Language	English
Publishing date	2015-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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