rmtОбщая реаниматологияGeneral Reanimatology1813-97792411-7110FSBI "SRIGR" RAMS10.15360/1813-9779-2018-3-46-53rmt-1690Research ArticleОБЗОРЫ И КРАТКИЕ СООБЩЕНИЯREVIEWS & SHORT COMMUNICATIONSНовые методы лечения при сепсисе: модели на животных «не работают» (обзор)New Approaches to Treat Sepsis: Animal Models «Do Not Work» (Review)КавайонЖ.-М.CavaillonJean-Marcjean-marc.cavaillon@pasteur.frИнститут ПастераРоссияInstitut PasteurRussian Federation2018020720181434653Copyright © Кавайон Ж., 20182018Кавайон Ж.Cavaillon J.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.reanimatology.com/rmt/article/view/1690

Сепсис, как и многие патологические инфекционные процессы, в основном изучается in vivo с использованием моделей на мышах. За последние 30 лет подобные исследования привели к значимым достижениям в понимании патофизиопатологии сепсиса. Однако, к сожалению, ни одно из них не привело к каким-либо «открытиям» в терапии пациентов. В настоящем обзоре мы ставим под сомнение актуальность используемых экспериментальных моделей, перечислим некоторые из редко принимаемых во внимание аспектов и обсудим пути выхода из создавшегося тупика. Ключевые слова: модели на животных; лечение сепсиса

Текст является переводом статьи Cavaillon J. M. Nouvelles therapies du sepsis: l'echec des modeles animaux, Bull. Assoc. Anc. El. Inst. Pasteur, 2017, 59, 230, 58—60. Перевод с французского выполнен фирмой «Академперевод», Москва, Россия.

Like many other pathological infectious processes, sepsis is mainly studied in vivo using mice models. Over the past 30 years, such studies have led to significant achievements in understanding of the sepsis pathophysiology. However, unfortunately, none of them led to any «discoveries» in the treatment of patients. In this review, we question the relevance of the experimental models applied, list some aspects rarely taken into account and discuss ways to resolve the deadlock.

The text is a translation of the article: Cavail-lon J. M. New methods of treating sepsis: failure of animal models, Bull. Assoc. Anc. El. Inst. Pastor, 2017, 59, 230, 58—60. Translation from French by «Akademperevod», Moscow, Russia.

модели на животныхлечение сепсисаanimal modeltreatment of sepsisReferencesBaker C.C., Chaudry I.H., Gaines H.O., Baue A.E. Evaluation of factors affecting mortality rate after sepsis in a murine cecal ligation and puncture model. Surgery. 1983; 94 (2): 331-335. PMID: 6879447Baker C.C., Chaudry I.H., Gaines H.O., Baue A.E. Evaluation of factors affecting mortality rate after sepsis in a murine cecal ligation and puncture model. Surgery. 1983; 94 (2): 331-335. PMID: 6879447Chaudry I.H., Hirasawa H., Baue A.E. Impairment of reticuloendothelial system function with sepsis and its improvement with ATP-MgCl2 plus glucose administration. Adv. Shock Res. 1979; 2: 153-162. PMID: 262800Chaudry I.H., Hirasawa H., Baue A.E. Impairment of reticuloendothelial system function with sepsis and its improvement with ATP-MgCl2 plus glucose administration. Adv. Shock Res. 1979; 2: 153-162. PMID: 262800Dejager L., Pinheiro I., Dejonckheere E., Libert C. Cecal ligation and puncture: the gold standard model for polymicrobial sepsis? Trends Microbiol. 2011; 19 (4): 198-208. DOI: 1016/j.tim.2011.01.001. PMID: 21296575Dejager L., Pinheiro I., Dejonckheere E., Libert C. Cecal ligation and puncture: the gold standard model for polymicrobial sepsis? Trends Microbiol. 2011; 19 (4): 198-208. DOI: 1016/j.tim.2011.01.001. PMID: 21296575Davaine C. Recherches sur les infusoires du sang dans la maladie connue sous le nom de sang de rate. C.R. Acad. Sci. 1863; 57: 220-223, 351-353.Davaine C. Recherches sur les infusoires du sang dans la maladie connue sous le nom de sang de rate. C.R. Acad. Sci. 1863; 57: 220-223, 351-353.Warren H.S., Fitting C., Hoff E., Adib-Conquy M., Beasley-Topliffe L., Tesini B., Liang X., Valentine C., Hellman J., Hayden D., Cavaillon J.M. Resilience to bacterial infection: difference between species could be due to proteins in serum. J. Infect. Dis. 2010; 201 (2): 223-232. DOI: 10.1086/649557. PMID: 20001600Warren H.S., Fitting C., Hoff E., Adib-Conquy M., Beasley-Topliffe L., Tesini B., Liang X., Valentine C., Hellman J., Hayden D., Cavaillon J.M. Resilience to bacterial infection: difference between species could be due to proteins in serum. J. Infect. Dis. 2010; 201 (2): 223-232. DOI: 10.1086/649557. PMID: 20001600Hajjar A.M., Ernst R.K., Tsai J.H., Wilson C.B., Miller S.I. Human toll-like receptor 4 recognizes host-specific LPS modifications. Nat. Immunol. 2002; 3 (4): 354-359. DOI: 10.1038/ni777. PMID: 11912497Hajjar A.M., Ernst R.K., Tsai J.H., Wilson C.B., Miller S.I. Human toll-like receptor 4 recognizes host-specific LPS modifications. Nat. Immunol. 2002; 3 (4): 354-359. DOI: 10.1038/ni777. PMID: 11912497Mora-Rillo M., Fernández-Romero N., Navarro-San Francisco C., DíezSebastián J., Romero-Gómez M.P., Fernández F.A., López J.R.A., Mingorance J. Impact of virulence genes on sepsis severity and survival in Escherichia coli bacteremia. Virulence. 2015; 6 (1): 93-100. DOI: 10.4161/21505594.2014.991234. PMID: 25654604Mora-Rillo M., Fernández-Romero N., Navarro-San Francisco C., DíezSebastián J., Romero-Gómez M.P., Fernández F.A., López J.R.A., Mingorance J. Impact of virulence genes on sepsis severity and survival in Escherichia coli bacteremia. Virulence. 2015; 6 (1): 93-100. DOI: 10.4161/21505594.2014.991234. PMID: 25654604Seboxa T., Amogne W., Abebe W., Tsegaye T., Azazh A., Hailu W., Fufa K., Grude N., Henriksen T.H. High mortality from blood stream infection in Addis Ababa, Ethiopia, is due to antimicrobial resistance. PLoS One. 2015; 10 (2): e0144944. DOI: 10.1371/journal.pone.0144944. PMID: 26670718Seboxa T., Amogne W., Abebe W., Tsegaye T., Azazh A., Hailu W., Fufa K., Grude N., Henriksen T.H. High mortality from blood stream infection in Addis Ababa, Ethiopia, is due to antimicrobial resistance. PLoS One. 2015; 10 (2): e0144944. DOI: 10.1371/journal.pone.0144944. PMID: 26670718Nguyen Q.T., Nguyen T.H., Ju S.A., Lee Y.S., Han S.H., Lee S.C., Kwon B.S., Yu R., Kim G.Y., Lee B.J., Kim B.S. CD137 expressed on neutrophils plays dual roles in antibacterial responses against Gram-positive and Gramnegative bacterial infections. Infect. Immun. 2013; 81 (6): 2168-2177. DOI: 10.1128/IAI.00115-13. PMID: 23545301Nguyen Q.T., Nguyen T.H., Ju S.A., Lee Y.S., Han S.H., Lee S.C., Kwon B.S., Yu R., Kim G.Y., Lee B.J., Kim B.S. CD137 expressed on neutrophils plays dual roles in antibacterial responses against Gram-positive and Gramnegative bacterial infections. Infect. Immun. 2013; 81 (6): 2168-2177. DOI: 10.1128/IAI.00115-13. PMID: 23545301Blanchet C., Jouvion G., Fitting C., Cavaillon J.M., Adib-Conquy M. Protective or deleterious role of scavenger receptors SR-A and CD36 on host resistance to Staphylococcus aureus depends on the site of infection. PLoS One. 2014; 9 (1): e87927. DOI: 10.1371/journal.pone.0087927. PMID: 24498223Blanchet C., Jouvion G., Fitting C., Cavaillon J.M., Adib-Conquy M. Protective or deleterious role of scavenger receptors SR-A and CD36 on host resistance to Staphylococcus aureus depends on the site of infection. PLoS One. 2014; 9 (1): e87927. DOI: 10.1371/journal.pone.0087927. PMID: 24498223Deng M., Scott M.J., Loughran P., Gibson G., Sodhi C., Watkins S., Hackam D., Billiar T.R. Lipopolysaccharide clearance, bacterial clearance, and systemic inflammatory responses are regulated by cell type-specific functions of TLR4 during sepsis. J. Immunol. 2013; 190 (10): 5152-5160. DOI: 10.4049/jimmunol.1300496. PMID: 23562812Deng M., Scott M.J., Loughran P., Gibson G., Sodhi C., Watkins S., Hackam D., Billiar T.R. Lipopolysaccharide clearance, bacterial clearance, and systemic inflammatory responses are regulated by cell type-specific functions of TLR4 during sepsis. J. Immunol. 2013; 190 (10): 5152-5160. DOI: 10.4049/jimmunol.1300496. PMID: 23562812Metzger D.W., Salmon S.L., Kirimanjeswara G. Differing effects of interleukin-10 on cutaneous and pulmonary Francisella tularensis live vaccine strain infection. Infect. Immun. 2013; 81 (6): 2022-2027. DOI: 10.1128/IAI.00024-13. PMID: 23529615Metzger D.W., Salmon S.L., Kirimanjeswara G. Differing effects of interleukin-10 on cutaneous and pulmonary Francisella tularensis live vaccine strain infection. Infect. Immun. 2013; 81 (6): 2022-2027. DOI: 10.1128/IAI.00024-13. PMID: 23529615von Köckritz-Blickwede M., Rohde M., Oehmcke S., Miller L.S., Cheung A.L., Herwald H., Foster S., Medina E. Immunological mechanisms underlying the genetic predisposition to severe Staphylococcus aureus infection in the mouse model. Am. J. Pathol. 2008; 173 (6): 1657-1668. DOI: 10.2353/ajpath.2008.080337. PMID: 18974303von Köckritz-Blickwede M., Rohde M., Oehmcke S., Miller L.S., Cheung A.L., Herwald H., Foster S., Medina E. Immunological mechanisms underlying the genetic predisposition to severe Staphylococcus aureus infection in the mouse model. Am. J. Pathol. 2008; 173 (6): 1657-1668. DOI: 10.2353/ajpath.2008.080337. PMID: 18974303Gingles N.A., Alexander J.E., Kadioglu A., Andrew P.W., Kerr A., Mitchell T.J., Hopes E., Denny P., Brown S., Jones H.B., Little S., Booth G.C., McPheat W.L. Role of genetic resistance in invasive pneumococcal infection: identification and study of susceptibility and resistance in inbred mouse strains. Infect. Immun. 2001; 69 (1): 426-434. DOI: 10.1128/IAI.69.1.426-434.2001. PMID: 11119534Gingles N.A., Alexander J.E., Kadioglu A., Andrew P.W., Kerr A., Mitchell T.J., Hopes E., Denny P., Brown S., Jones H.B., Little S., Booth G.C., McPheat W.L. Role of genetic resistance in invasive pneumococcal infection: identification and study of susceptibility and resistance in inbred mouse strains. Infect. Immun. 2001; 69 (1): 426-434. DOI: 10.1128/IAI.69.1.426-434.2001. PMID: 11119534De Albuquerque N., Baig E., Ma X., Zhang J., He W., Rowe A., Habal M., Liu M., Shalev I., Downey G.P., Gorczynski R., Butany J., Leibowitz J., Weiss S.R., McGilvray I.D., Phillips M.J., Fish E.N., Levy G.A. Murine hepatitis virus strain 1 produces a clinically relevant model of severe acute respiratory syndrome in A/J mice. J. Virol. 2006; 80 (21): 10382-10394. DOI: 10.1128/JVI.00747-06. PMID: 17041219De Albuquerque N., Baig E., Ma X., Zhang J., He W., Rowe A., Habal M., Liu M., Shalev I., Downey G.P., Gorczynski R., Butany J., Leibowitz J., Weiss S.R., McGilvray I.D., Phillips M.J., Fish E.N., Levy G.A. Murine hepatitis virus strain 1 produces a clinically relevant model of severe acute respiratory syndrome in A/J mice. J. Virol. 2006; 80 (21): 10382-10394. DOI: 10.1128/JVI.00747-06. PMID: 17041219Watanabe H., Numata K., Ito T., Takagi K., Matsukawa A. Innate immune response in Th1and Th2-dominant mouse strains. Shock. 2004; 22 (5): 460-466. DOI: 10.1097/01.shk.0000142249.08135.e9. PMID: 15489639Watanabe H., Numata K., Ito T., Takagi K., Matsukawa A. Innate immune response in Th1and Th2-dominant mouse strains. Shock. 2004; 22 (5): 460-466. DOI: 10.1097/01.shk.0000142249.08135.e9. PMID: 15489639Hultgren O., Kopf M., Tarkowski A. Outcome of Staphylococcus aureustriggered sepsis and arthritis in IL-4-deficient mice depends on the genetic background of the host. Eur. J. Immunol. 1999; 29 (8): 2400-2405. DOI: 10.1002/(SICI)1521-4141(199908)29:083.0.CO;2-E. PMID: 10458752Hultgren O., Kopf M., Tarkowski A. Outcome of Staphylococcus aureustriggered sepsis and arthritis in IL-4-deficient mice depends on the genetic background of the host. Eur. J. Immunol. 1999; 29 (8): 2400-2405. DOI: 10.1002/(SICI)1521-4141(199908)29:083.0.CO;2-E. PMID: 10458752Wells C.A., Ravasi T., Faulkner G.J., Carninci P., Okazaki Y., Hayashizaki Y., Sweet M., Wainwright B.J., Hume D.A. Genetic control of the innate immune response. BMC Immunol. 2003; 4: 5-22. DOI: 10.1186/14712172-4-5. PMID: 12826024Wells C.A., Ravasi T., Faulkner G.J., Carninci P., Okazaki Y., Hayashizaki Y., Sweet M., Wainwright B.J., Hume D.A. Genetic control of the innate immune response. BMC Immunol. 2003; 4: 5-22. DOI: 10.1186/14712172-4-5. PMID: 12826024Klein S.L., Flanagan K.L. Sex differences in immune responses. Nat. Rev. Immunol. 2016; 16 (10): 626-638. DOI: 10.1038/nri.2016.90. PMID: 27546235Klein S.L., Flanagan K.L. Sex differences in immune responses. Nat. Rev. Immunol. 2016; 16 (10): 626-638. DOI: 10.1038/nri.2016.90. PMID: 27546235Pasche B., Kalaydjiev S., Franz T.J., Kremmer E., Gailus-Durner V., Fuchs H., Hrabé de Angelis M., Lengeling A., Busch D.H. Sex-dependent susceptibility to Listeria monocytogenes infection is mediated by differential interleukin-10 production. Infect. Immun. 2005; 73 (9): 5952-5960. DOI: 10.1128/IAI.73.9.5952-5960.2005. PMID: 16113316Pasche B., Kalaydjiev S., Franz T.J., Kremmer E., Gailus-Durner V., Fuchs H., Hrabé de Angelis M., Lengeling A., Busch D.H. Sex-dependent susceptibility to Listeria monocytogenes infection is mediated by differential interleukin-10 production. Infect. Immun. 2005; 73 (9): 5952-5960. DOI: 10.1128/IAI.73.9.5952-5960.2005. PMID: 16113316Zellweger R., Wichmann M.W., Ayala A., Stein S., DeMaso C.M., Chaudry I.H. Females in proestrus state maintain splenic immune functions and tolerate sepsis better than males. Crit. Care Med. 1997; 25 (1): 106-110. DOI: 10.1097/00003246-199701000-00021. PMID: 8989185Zellweger R., Wichmann M.W., Ayala A., Stein S., DeMaso C.M., Chaudry I.H. Females in proestrus state maintain splenic immune functions and tolerate sepsis better than males. Crit. Care Med. 1997; 25 (1): 106-110. DOI: 10.1097/00003246-199701000-00021. PMID: 8989185Harizi H., Homo-Delarche F., Amrani A., Coulaud J., Mormède P. Marked genetic differences in the regulation of blood glucose under immune and restraint stress in mice reveals a wide range of corticosensitivity. J. Neuroimmunol. 2007; 189 (1-2): 59-68. DOI: 10.1016/j.jneuroim.2007.06.019. PMID: 17658621Harizi H., Homo-Delarche F., Amrani A., Coulaud J., Mormède P. Marked genetic differences in the regulation of blood glucose under immune and restraint stress in mice reveals a wide range of corticosensitivity. J. Neuroimmunol. 2007; 189 (1-2): 59-68. DOI: 10.1016/j.jneuroim.2007.06.019. PMID: 17658621Tateda K., Matsumoto T., Miyazaki S., Yamaguchi K. Lipopolysaccharideinduced lethality and cytokine production in aged mice. Infect. Immun. 1996; 64 (3): 769-774. PMID: 8641780Tateda K., Matsumoto T., Miyazaki S., Yamaguchi K. Lipopolysaccharideinduced lethality and cytokine production in aged mice. Infect. Immun. 1996; 64 (3): 769-774. PMID: 8641780Saito H., Sherwood E.R., Varma T.K., Evers B.M. Effects of aging on mortality, hypothermia, and cytokine induction in mice with endotoxemia or sepsis. Mech. Ageing Dev. 2003; 124 (10-12): 1047-1058. DOI: 10.1016/j.mad.2003.08.002. PMID: 14659593Saito H., Sherwood E.R., Varma T.K., Evers B.M. Effects of aging on mortality, hypothermia, and cytokine induction in mice with endotoxemia or sepsis. Mech. Ageing Dev. 2003; 124 (10-12): 1047-1058. DOI: 10.1016/j.mad.2003.08.002. PMID: 14659593Starr M.E., Evers B.M., Saito H. Age-associated increase in cytokine production during systemic inflammation: adipose tissue as a major source of IL-6. J. Gerontol. A Biol. Sci. Med. Sci. 2009; 64 (7): 723-730. DOI: 10.1093/gerona/glp046. PMID: 19377014 2Starr M.E., Evers B.M., Saito H. Age-associated increase in cytokine production during systemic inflammation: adipose tissue as a major source of IL-6. J. Gerontol. A Biol. Sci. Med. Sci. 2009; 64 (7): 723-730. DOI: 10.1093/gerona/glp046. PMID: 19377014 2Mirsoian A., Bouchlaka M.N., Sckisel G.D., Chen M., Pai C.C., Maverakis E., Spencer R.G., Fishbein K.W., Siddiqui S., Monjazeb A.M., Martin B., Maudsley S., Hesdorffer C., Ferrucci L., Longo D.L., Blazar B.R., Wiltrout R.H., Taub D.D., Murphy W.J. Adiposity induces lethal cytokine storm after systemic administration of stimulatory immunotherapy regimens in aged mice. J. Exp. Med. 2014; 211 (12): 2373-2383. DOI: 10.1084/jem.20140116. PMID: 25366964Mirsoian A., Bouchlaka M.N., Sckisel G.D., Chen M., Pai C.C., Maverakis E., Spencer R.G., Fishbein K.W., Siddiqui S., Monjazeb A.M., Martin B., Maudsley S., Hesdorffer C., Ferrucci L., Longo D.L., Blazar B.R., Wiltrout R.H., Taub D.D., Murphy W.J. Adiposity induces lethal cytokine storm after systemic administration of stimulatory immunotherapy regimens in aged mice. J. Exp. Med. 2014; 211 (12): 2373-2383. DOI: 10.1084/jem.20140116. PMID: 25366964Lambeck S., Weber M., Gonnert F.A., Mrowka R., Bauer M. Comparison of sepsis-induced transcriptomic changes in a murine model to clinical blood samples identifies common response patterns. Front. Microbiol. 2012; 3: 284. DOI: 10.3389/fmicb.2012.00284. PMID: 23024636Lambeck S., Weber M., Gonnert F.A., Mrowka R., Bauer M. Comparison of sepsis-induced transcriptomic changes in a murine model to clinical blood samples identifies common response patterns. Front. Microbiol. 2012; 3: 284. DOI: 10.3389/fmicb.2012.00284. PMID: 23024636Scheiermann C., Kunisaki Y., Lucas D., Chow A., Jang J.E., Zhang D., Hashimoto D., Merad M., Frenette P.S. Adrenergic nerves govern circadian leukocyte recruitment to tissues. Immunity. 2012; 37 (2): 290-301. DOI: 10.1016/j.immuni.2012.05.021. PMID: 22863835Scheiermann C., Kunisaki Y., Lucas D., Chow A., Jang J.E., Zhang D., Hashimoto D., Merad M., Frenette P.S. Adrenergic nerves govern circadian leukocyte recruitment to tissues. Immunity. 2012; 37 (2): 290-301. DOI: 10.1016/j.immuni.2012.05.021. PMID: 22863835Castanon-Cervantes O., Wu M., Ehlen J.C., Paul K., Gamble K.L., Johnson R.L., Besing R.C., Menaker M., Gewirtz A.T., Davidson A.J. Dysregulation of inflammatory responses by chronic circadian disruption. J. Immunol. 2010; 185 (10): 5796-5805. DOI: 10.4049/jimmunol.1001026. PMID: 20944004Castanon-Cervantes O., Wu M., Ehlen J.C., Paul K., Gamble K.L., Johnson R.L., Besing R.C., Menaker M., Gewirtz A.T., Davidson A.J. Dysregulation of inflammatory responses by chronic circadian disruption. J. Immunol. 2010; 185 (10): 5796-5805. DOI: 10.4049/jimmunol.1001026. PMID: 20944004Martin B., Ji S., Maudsley S., Mattson M.P. «Control» laboratory rodents are metabolically morbid: why it matters. Proc. Natl. Acad. Sci. U S A. 2010; 107 (14): 6127-6133. DOI: 10.1073/pnas.0912955107. PMID: 20194732Martin B., Ji S., Maudsley S., Mattson M.P. «Control» laboratory rodents are metabolically morbid: why it matters. Proc. Natl. Acad. Sci. U S A. 2010; 107 (14): 6127-6133. DOI: 10.1073/pnas.0912955107. PMID: 20194732Gordon C. Thermal physiology of laboratory mice: defining thermoneutrality. J. Thermal. Biology. 2012; 37: 654-685.Gordon C. Thermal physiology of laboratory mice: defining thermoneutrality. J. Thermal. Biology. 2012; 37: 654-685.Karp C.L. Unstressing intemperate models: how cold stress undermines mouse modeling. J. Exp. Med. 2012; 209 (6): 1069-1074. DOI: 10.1084/jem.20120988. PMID: 22665703Karp C.L. Unstressing intemperate models: how cold stress undermines mouse modeling. J. Exp. Med. 2012; 209 (6): 1069-1074. DOI: 10.1084/jem.20120988. PMID: 22665703Jiang Q., Cross A.S., Singh I.S., Chen T.T., Viscardi R.M., Hasday J.D. Febrile core temperature is essential for optimal host defense in bacterial peritonitis. Infect. Immun. 2000; 68 (3): 1265-1270. DOI: 10.1128/IAI.68.3.1265-1270.2000. PMID: 10678936Jiang Q., Cross A.S., Singh I.S., Chen T.T., Viscardi R.M., Hasday J.D. Febrile core temperature is essential for optimal host defense in bacterial peritonitis. Infect. Immun. 2000; 68 (3): 1265-1270. DOI: 10.1128/IAI.68.3.1265-1270.2000. PMID: 10678936Mestas J., Hughes C.C. Of mice and not men: differences between mouse and human immunology. J. Immunol. 2004; 172 (5): 2731-2738. DOI: 10.4049/jimmunol.172.5.2731. PMID: 14978070Mestas J., Hughes C.C. Of mice and not men: differences between mouse and human immunology. J. Immunol. 2004; 172 (5): 2731-2738. DOI: 10.4049/jimmunol.172.5.2731. PMID: 14978070Ong G.L., Mattes M.J. Mouse strains with typical mammalian levels of complement activity. J. Immunol. Methods. 1989; 125 (1-2): 147-158. DOI: 10.1016/0022-1759(89)90088-4. PMID: 2607149Ong G.L., Mattes M.J. Mouse strains with typical mammalian levels of complement activity. J. Immunol. Methods. 1989; 125 (1-2): 147-158. DOI: 10.1016/0022-1759(89)90088-4. PMID: 2607149Ratelade J., Verkman A.S. Inhibitor(s) of the classical complement pathway in mouse serum limit the utility of mice as experimental models of neuromyelitis optica. Mol. Immunol. 2014; 62 (1): 104-113. DOI: 10.1016/j.molimm.2014.06.003. PMID: 24980869Ratelade J., Verkman A.S. Inhibitor(s) of the classical complement pathway in mouse serum limit the utility of mice as experimental models of neuromyelitis optica. Mol. Immunol. 2014; 62 (1): 104-113. DOI: 10.1016/j.molimm.2014.06.003. PMID: 24980869Limaye A.P., Kirby K.A., Rubenfeld G.D., Leisenring W.M., Bulger E.M., Neff M.J., Gibran N.S., Huang M.L., Santo Hayes T.K., Corey L., Boeckh M. Cytomegalovirus reactivation in critically ill immunocompetent patients. JAMA. 2008; 300 (4): 413-422. DOI: 10.1001/jama.300.4.413. PMID: 18647984Limaye A.P., Kirby K.A., Rubenfeld G.D., Leisenring W.M., Bulger E.M., Neff M.J., Gibran N.S., Huang M.L., Santo Hayes T.K., Corey L., Boeckh M. Cytomegalovirus reactivation in critically ill immunocompetent patients. JAMA. 2008; 300 (4): 413-422. DOI: 10.1001/jama.300.4.413. PMID: 18647984Luyt C.E., Combes A., Deback C., Aubriot-Lorton M.H., Nieszkowska A., Trouillet J.L., Capron F., Agut H., Gibert C., Chastre J. Herpes simplex virus lung infection in patients undergoing prolonged mechanical ventilation. Am. J. Respir. Crit. Care Med. 2007; 175 (9): 935-942. DOI: 10.1164/rccm.200609-1322OC. PMID: 17234903Luyt C.E., Combes A., Deback C., Aubriot-Lorton M.H., Nieszkowska A., Trouillet J.L., Capron F., Agut H., Gibert C., Chastre J. Herpes simplex virus lung infection in patients undergoing prolonged mechanical ventilation. Am. J. Respir. Crit. Care Med. 2007; 175 (9): 935-942. DOI: 10.1164/rccm.200609-1322OC. PMID: 17234903Alonso J.M., Guiyoule A., Zarantonelli M.L., Ramisse F., Pires R., Antignac A., Deghmane A.E., Huerre M., van der Werf S., Taha M.K. A model of meningococcal bacteremia after respiratory superinfection in influenza a virus-infected mice. FEMS Microbiol Lett. 2003; 222 (1): 99-106. DOI: 10.1016/S0378-1097(03)00252-0. PMID: 12757952Alonso J.M., Guiyoule A., Zarantonelli M.L., Ramisse F., Pires R., Antignac A., Deghmane A.E., Huerre M., van der Werf S., Taha M.K. A model of meningococcal bacteremia after respiratory superinfection in influenza a virus-infected mice. FEMS Microbiol Lett. 2003; 222 (1): 99-106. DOI: 10.1016/S0378-1097(03)00252-0. PMID: 12757952Nansen A., Christensen J.P., Marker O., Thomsen A.R. Sensitization to lipopolysaccharide in mice with asymptomatic viral infection: role of T cell-dependent production of interferon-gamma. J. Infect. Dis. 1997; 176 (1): 151-157. DOI: 10.1086/514017. PMID: 9207361Nansen A., Christensen J.P., Marker O., Thomsen A.R. Sensitization to lipopolysaccharide in mice with asymptomatic viral infection: role of T cell-dependent production of interferon-gamma. J. Infect. Dis. 1997; 176 (1): 151-157. DOI: 10.1086/514017. PMID: 9207361Speshock J.L., Doyon-Reale N., Rabah R., Neely M.N., Roberts P.C. Filamentous influenza A virus infection predisposes mice to fatal septicemia following superinfection with Streptococcus pneumoniae serotype 3. Infect. Immun. 2007; 75: 3102-3111. DOI: 10.1128/IAI.01943-06. PMID: 17403870Speshock J.L., Doyon-Reale N., Rabah R., Neely M.N., Roberts P.C. Filamentous influenza A virus infection predisposes mice to fatal septicemia following superinfection with Streptococcus pneumoniae serotype 3. Infect. Immun. 2007; 75: 3102-3111. DOI: 10.1128/IAI.01943-06. PMID: 17403870Salgado-Pabón W., Breshears L., Spaulding A.R., Merriman J.A., Stach C.S., Horswill A.R., Peterson M.L., Schlievert P.M. Superantigens are critical for Staphylococcus aureus infective endocarditis, sepsis, and acute kidney injury. MBio. 2013; 4 (4): pii: e00494-13. DOI: 10.1128/mBio.00494-13. PMID: 23963178Salgado-Pabón W., Breshears L., Spaulding A.R., Merriman J.A., Stach C.S., Horswill A.R., Peterson M.L., Schlievert P.M. Superantigens are critical for Staphylococcus aureus infective endocarditis, sepsis, and acute kidney injury. MBio. 2013; 4 (4): pii: e00494-13. DOI: 10.1128/mBio.00494-13. PMID: 23963178Fairbairn L., Kapetanovic R., Beraldi D., Sester D.P., Tuggle C.K., Archibald A.L., Hume D.A. Comparative analysis of monocyte subsets in the pig. J. Immunol. 2013; 190 (12): 6389-6396. DOI: 10.4049/jimmunol.1300365. PMID: 23667115Fairbairn L., Kapetanovic R., Beraldi D., Sester D.P., Tuggle C.K., Archibald A.L., Hume D.A. Comparative analysis of monocyte subsets in the pig. J. Immunol. 2013; 190 (12): 6389-6396. DOI: 10.4049/jimmunol.1300365. PMID: 23667115Kapetanovic R., Fairbairn L., Beraldi D., Sester D.P., Archibald A.L., Tuggle C.K., Hume D.A. Pig bone marrow-derived macrophages resemble human macrophages in their response to bacterial lipopolysaccharide. J. Immunol. 2012; 188 (7): 3382-3394. DOI: 10.4049/jimmunol.1102649. PMID: 22393154Kapetanovic R., Fairbairn L., Beraldi D., Sester D.P., Archibald A.L., Tuggle C.K., Hume D.A. Pig bone marrow-derived macrophages resemble human macrophages in their response to bacterial lipopolysaccharide. J. Immunol. 2012; 188 (7): 3382-3394. DOI: 10.4049/jimmunol.1102649. PMID: 22393154Barreiro L.B., Marioni J.C., Blekhman R., Stephens M., Gilad Y. Functional comparison of innate immune signaling pathways in primates. PLoS Genet. 2010; 6 (12): e1001249. DOI: 10.1371/journal.pgen.1001249. PMID: 21187902Barreiro L.B., Marioni J.C., Blekhman R., Stephens M., Gilad Y. Functional comparison of innate immune signaling pathways in primates. PLoS Genet. 2010; 6 (12): e1001249. DOI: 10.1371/journal.pgen.1001249. PMID: 21187902Brinkworth J.F., Pechenkina E.A., Silver J., Goyert S.M. Innate immune responses to TLR2 and TLR4 agonists differ between baboons, chimpanzees and humans. J. Med. Primatol. 2012; 41 (6): 388-393. DOI: 10.1111/jmp.12002. PMID: 22978822Brinkworth J.F., Pechenkina E.A., Silver J., Goyert S.M. Innate immune responses to TLR2 and TLR4 agonists differ between baboons, chimpanzees and humans. J. Med. Primatol. 2012; 41 (6): 388-393. DOI: 10.1111/jmp.12002. PMID: 22978822Melican K., Michea Veloso P., Martin T., Bruneval P., Duménil G. Adhesion of Neisseria meningitidis to dermal vessels leads to local vascular damage and purpura in a humanized mouse model. PLoS Pathog. 2013; 9 (1): e1003139. DOI: 10.1371/journal.ppat.1003139. PMID: 23359320Melican K., Michea Veloso P., Martin T., Bruneval P., Duménil G. Adhesion of Neisseria meningitidis to dermal vessels leads to local vascular damage and purpura in a humanized mouse model. PLoS Pathog. 2013; 9 (1): e1003139. DOI: 10.1371/journal.ppat.1003139. PMID: 23359320Rongvaux A., Willinger T., Martinek J., Strowig T., Gearty S.V., Teichmann L.L., Saito Y., Marches F., Halene S., Palucka A.K., Manz M.G., Flavell R.A. Development and function of human innate immune cells in a humanized mouse model. Nat. Biotechnol. 2014; 32 (4): 364-372. DOI: 10.1038/nbt.2858. PMID: 24633240Rongvaux A., Willinger T., Martinek J., Strowig T., Gearty S.V., Teichmann L.L., Saito Y., Marches F., Halene S., Palucka A.K., Manz M.G., Flavell R.A. Development and function of human innate immune cells in a humanized mouse model. Nat. Biotechnol. 2014; 32 (4): 364-372. DOI: 10.1038/nbt.2858. PMID: 24633240Huh D., Kim H.J., Fraser J.P., Shea D.E., Khan M., Bahinski A., Hamilton G.A., Ingber D.E. Microfabrication of human organs-on-chips. Nat. Protoc. 2013; 8 (11): 2135-2157. DOI: 10.1038/nprot.2013.137. PMID: 24113786Huh D., Kim H.J., Fraser J.P., Shea D.E., Khan M., Bahinski A., Hamilton G.A., Ingber D.E. Microfabrication of human organs-on-chips. Nat. Protoc. 2013; 8 (11): 2135-2157. DOI: 10.1038/nprot.2013.137. PMID: 24113786Lancaster M.A., Knoblich J.A. Organogenesis in a dish: modeling development and disease using organoid technologies. Science. 2014; 345 (6194): 1247125. DOI: 10.1126/science.1247125. PMID: 25035496Lancaster M.A., Knoblich J.A. Organogenesis in a dish: modeling development and disease using organoid technologies. Science. 2014; 345 (6194): 1247125. DOI: 10.1126/science.1247125. PMID: 25035496Zhang Y.G., Wu S., Xia Y., Sun J. Salmonella-infected crypt-derived intestinal organoid culture system for host-bacterial interactions. Physiol. Rep. 2014; 2 (9): pii: e12147. DOI: 10.14814/phy2.12147. PMID: 25214524Zhang Y.G., Wu S., Xia Y., Sun J. Salmonella-infected crypt-derived intestinal organoid culture system for host-bacterial interactions. Physiol. Rep. 2014; 2 (9): pii: e12147. DOI: 10.14814/phy2.12147. PMID: 25214524Efron P.A., Mohr A.M., Moore F.A., Moldawer L.L. The future of murine sepsis and trauma research models. J. Leukoc. Biol. 2015; 98 (6): 945-952. DOI: 10.1189/jlb.5MR0315-127R. PMID: 26034205Efron P.A., Mohr A.M., Moore F.A., Moldawer L.L. The future of murine sepsis and trauma research models. J. Leukoc. Biol. 2015; 98 (6): 945-952. DOI: 10.1189/jlb.5MR0315-127R. PMID: 26034205Hotchkiss R.S., Monneret G., Payen D. Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat. Rev. Immunol. 2013; 13 (12): 862-874. DOI: 10.1038/nri3552. PMID: 24232462Hotchkiss R.S., Monneret G., Payen D. Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat. Rev. Immunol. 2013; 13 (12): 862-874. DOI: 10.1038/nri3552. PMID: 24232462Suzuki T., Shimizu T., Szalay L., Choudhry M.A., Rue L.W.3rd, Bland K.I., Chaudry I.H. Androstenediol ameliorates alterations in immune cells cytokine production capacity in a two-hit model of trauma-hemorrhage and sepsis. Cytokine. 2006; 34 (1-2): 76-84. DOI: 10.1016/j.cyto.2006.04.007. PMID: 16737821Suzuki T., Shimizu T., Szalay L., Choudhry M.A., Rue L.W.3rd, Bland K.I., Chaudry I.H. Androstenediol ameliorates alterations in immune cells cytokine production capacity in a two-hit model of trauma-hemorrhage and sepsis. Cytokine. 2006; 34 (1-2): 76-84. DOI: 10.1016/j.cyto.2006.04.007. PMID: 16737821Cavaillon J.M., Eisen D., Annane D. Is boosting the immune system in sepsis appropriate? Crit. Care. 2014; 18 (2): 216-225. DOI: 10.1186/cc13787. PMID: 24886820Cavaillon J.M., Eisen D., Annane D. Is boosting the immune system in sepsis appropriate? Crit. Care. 2014; 18 (2): 216-225. DOI: 10.1186/cc13787. PMID: 24886820

The authors declare that there are no conflicts of interest present.