• The 3D structure of Kaposi sarcoma herpesvirus LANA C-terminal domain bound to DNA.

      Hellert, Jan; Weidner-Glunde, Magdalena; Krausze, Joern; Lünsdorf, Heinrich; Ritter, Christiane; Schulz, Thomas F; Lührs, Thorsten (2015-05-26)
      Kaposi sarcoma herpesvirus (KSHV) persists as a latent nuclear episome in dividing host cells. This episome is tethered to host chromatin to ensure proper segregation during mitosis. For duplication of the latent genome, the cellular replication machinery is recruited. Both of these functions rely on the constitutively expressed latency-associated nuclear antigen (LANA) of the virus. Here, we report the crystal structure of the KSHV LANA DNA-binding domain (DBD) in complex with its high-affinity viral target DNA, LANA binding site 1 (LBS1), at 2.9 Å resolution. In contrast to homologous proteins such as Epstein-Barr virus nuclear antigen 1 (EBNA-1) of the related γ-herpesvirus Epstein-Barr virus, specific DNA recognition by LANA is highly asymmetric. In addition to solving the crystal structure, we found that apart from the two known LANA binding sites, LBS1 and LBS2, LANA also binds to a novel site, denoted LBS3. All three sites are located in a region of the KSHV terminal repeat subunit previously recognized as a minimal replicator. Moreover, we show that the LANA DBD can coat DNA of arbitrary sequence by virtue of a characteristic lysine patch, which is absent in EBNA-1 of the Epstein-Barr virus. Likely, these higher-order assemblies involve the self-association of LANA into supermolecular spirals. One such spiral assembly was solved as a crystal structure of 3.7 Å resolution in the absence of DNA. On the basis of our data, we propose a model for the controlled nucleation of higher-order LANA oligomers that might contribute to the characteristic subnuclear KSHV microdomains ("LANA speckles"), a hallmark of KSHV latency.
    • Absence of regulator of G-protein signaling 4 does not protect against dopamine neuron dysfunction and injury in the mouse 6-hydroxydopamine lesion model of Parkinson's disease.

      Ashrafi, Amer; Garcia, Pierre; Kollmus, Heike; Schughart, Klaus; Del Sol, Antonio; Buttini, Manuel; Glaab, Enrico; HelmholtzCentre of infetion research, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2017-06-19)
      Regulator of G-protein signaling 4 (RGS4), a member of the RGS family of proteins that inactivate G-proteins, has gained interest as a potential drug target for neurological disorders, such as epilepsy and Parkinson's disease (PD). In the case of PD, the main current options for alleviating motor symptoms are dopamine replacement therapies, which have limitations because of side effects and reduced effectiveness over the long term. Research on new nondopaminergic PD drug targets has indicated that inhibition of RGS4 could be an effective adjuvant treatment option. The effectiveness of RGS4 inhibition for an array of PD-linked functional and structural neuroprotection end points has not yet been demonstrated. Here, we use the 6-hydroxydopamine (6-OHDA) lesioning model of the nigrostriatal pathway in mice to address this question. We observe, using a battery of behavioral and pathological measures, that mice deficient for RGS4 are not protected from 6-OHDA-induced injury and show enhanced susceptibility in some measures of motor function. Our results suggest that inhibition of RGS4 as a nondopaminergic target for PD should be approached with caution.
    • Analysis of Jmjd6 cellular localization and testing for its involvement in histone demethylation.

      Hahn, Phillip; Wegener, Ivonne; Burrells, Alison; Böse, Jens; Wolf, Alexander; Erck, Christian; Butler, Danica; Schofield, Christopher J; Böttger, Angelika; Lengeling, Andreas; et al. (2010)
      BACKGROUND: Methylation of residues in histone tails is part of a network that regulates gene expression. JmjC domain containing proteins catalyze the oxidative removal of methyl groups on histone lysine residues. Here, we report studies to test the involvement of Jumonji domain-containing protein 6 (Jmjd6) in histone lysine demethylation. Jmjd6 has recently been shown to hydroxylate RNA splicing factors and is known to be essential for the differentiation of multiple tissues and cells during embryogenesis. However, there have been conflicting reports as to whether Jmjd6 is a histone-modifying enzyme. METHODOLOGY/PRINCIPAL FINDINGS: Immunolocalization studies reveal that Jmjd6 is distributed throughout the nucleoplasm outside of regions containing heterochromatic DNA, with occasional localization in nucleoli. During mitosis, Jmjd6 is excluded from the nucleus and reappears in the telophase of the cell cycle. Western blot analyses confirmed that Jmjd6 forms homo-multimers of different molecular weights in the nucleus and cytoplasm. A comparison of mono-, di-, and tri-methylation states of H3K4, H3K9, H3K27, H3K36, and H4K20 histone residues in wildtype and Jmjd6-knockout cells indicate that Jmjd6 is not involved in the demethylation of these histone lysine residues. This is further supported by overexpression of enzymatically active and inactive forms of Jmjd6 and subsequent analysis of histone methylation patterns by immunocytochemistry and western blot analysis. Finally, treatment of cells with RNase A and DNase I indicate that Jmjd6 may preferentially associate with RNA/RNA complexes and less likely with chromatin. CONCLUSIONS/SIGNIFICANCE: Taken together, our results provide further evidence that Jmjd6 is unlikely to be involved in histone lysine demethylation. We confirmed that Jmjd6 forms multimers and showed that nuclear localization of the protein involves association with a nucleic acid matrix.
    • Antiviral potential of human IFN-α subtypes against influenza A H3N2 infection in human lung explants reveals subtype-specific activities.

      Matos, Aline da Rocha; Wunderlich, Katharina; Schloer, Sebastian; Schughart, Klaus; Geffers, Robert; Seders, Martine; Witt, Marlous de; Christersson, Anmari; Wiewrodt, Rainer; Wiebe, Karsten; et al. (Taylor & Francis Open, 2019-01-01)
      Influenza is an acute respiratory infection causing high morbidity and mortality in annual outbreaks worldwide. Antiviral drugs are limited and pose the risk of resistance development, calling for new treatment options. IFN-α subtypes are immune-stimulatory cytokines with strong antiviral activities against IAV in vitro and in vivo. However, the clinical use of IFN-α2, the only licensed subtype of this multi-gene family, could not prevent or limit IAV infections in humans. However, the other subtypes were not investigated.Therefore, this study evaluated the induction and antiviral potential of all human IFN-α subtypes during H3N2 IAV infection in human lung explants. We found that subtypes with weak antiviral activities were preferentially induced during IAV infection in human lungs. Intriguingly, non-induced subtypes α16, α5 and α4 suppressed viral replication up to 230-fold more efficiently than α2. Furthermore, our results demonstrate that subtypes with stronger antiviral activities induce higher expression of IAV-specific restriction factors and that MxA expression is a determinant of the subtype-specific antiviral activity towards H3N2 IAV. These results corroborate that IFN-α subtypes exhibit differential antiviral activities and emphasize that subtypes α16, α5 and α4 should be further investigated for the prevention and treatment of severe infections with seasonal H3N2 IAV.
    • ATR-FTIR spectroscopy reveals genomic loci regulating the tissue response in high fat diet fed BXD recombinant inbred mouse strains.

      Lasch, Peter; Neuschl, Christina; Millrose, Marion K; Alberts, Rudi; Schughart, Klaus; Naumann, Dieter; Brockmann, Gudrun A; Department for Crop and Animal Sciences, Humboldt-Universität zu Berlin, Invalidenstraße 42, 10115, Berlin, Germany. (2013)
      Obesity-associated organ-specific pathological states can be ensued from the dysregulation of the functions of the adipose tissues, liver and muscle. However, the influence of genetic differences underlying gross-compositional differences in these tissues is largely unknown. In the present study, the analytical method of ATR-FTIR spectroscopy has been combined with a genetic approach to identify genetic differences responsible for phenotypic alterations in adipose, liver and muscle tissues.
    • Bioinformatics tools and database resources for systems genetics analysis in mice--a short review and an evaluation of future needs.

      Durrant, Caroline; Swertz, Morris A; Alberts, Rudi; Arends, Danny; Möller, Steffen; Mott, Richard; Prins, Pjotr; van der Velde, K Joeri; Jansen, Ritsert C; Schughart, Klaus; et al. (2012-03)
      During a meeting of the SYSGENET working group 'Bioinformatics', currently available software tools and databases for systems genetics in mice were reviewed and the needs for future developments discussed. The group evaluated interoperability and performed initial feasibility studies. To aid future compatibility of software and exchange of already developed software modules, a strong recommendation was made by the group to integrate HAPPY and R/qtl analysis toolboxes, GeneNetwork and XGAP database platforms, and TIQS and xQTL processing platforms. R should be used as the principal computer language for QTL data analysis in all platforms and a 'cloud' should be used for software dissemination to the community. Furthermore, the working group recommended that all data models and software source code should be made visible in public repositories to allow a coordinated effort on the use of common data structures and file formats.
    • The bioluminescent Listeria monocytogenes strain Xen32 is defective in flagella expression and highly attenuated in orally infected BALB/cJ mice.

      Bergmann, Silke; Rohde, Manfred; Schughart, Klaus; Lengeling, Andreas; Helmholtz Centre for infection research, Inhoffenstr. 7, D-38124 Braunschweig, Germany. (2013)
      In vivo bioluminescence imaging (BLI) is a powerful method for the analysis of host-pathogen interactions in small animal models. The commercially available bioluminescent Listeria monocytogenes strain Xen32 is commonly used to analyse immune functions in knockout mice and pathomechanisms of listeriosis.
    • Cellular changes in blood indicate severe respiratory disease during influenza infections in mice.

      Dengler, Leonie; Kühn, Nora; Shin, Dai-Lun; Hatesuer, Bastian; Schughart, Klaus; Wilk, Esther (2014)
      Influenza A infection is a serious threat to human and animal health. Many of the biological mechanisms of the host-pathogen-interactions are still not well understood and reliable biomarkers indicating the course of the disease are missing. The mouse is a valuable model system enabling us to study the local inflammatory host response and the influence on blood parameters under controlled circumstances. Here, we compared the lung and peripheral changes after PR8 (H1N1) influenza A virus infection in C57BL/6J and DBA/2J mice using virus variants of different pathogenicity resulting in non-lethal and lethal disease. We monitored hematological and immunological parameters revealing that the granulocyte to lymphocyte ratio in the blood represents an early indicator of severe disease progression already two days after influenza A infection in mice. These findings might be relevant to optimize early diagnostic options of severe influenza disease and to monitor successful therapeutic treatment in humans.
    • A comprehensive and comparative phenotypic analysis of the collaborative founder strains identifies new and known phenotypes.

      Kollmus, Heike; Fuchs, Helmut; Lengger, Christoph; Haselimashhadi, Hamed; Bogue, Molly A; Östereicher, Manuela A; Horsch, Marion; Adler, Thure; Aguilar-Pimentel, Juan Antonio; Amarie, Oana Veronica; et al. (Springer, 2020-02-14)
      Myxococcus xanthus DK1622 is known as a proficient producer of different kinds of secondary metabolites (SM) with various biological activities, including myxovirescin A, myxalamide A, myxochromide A and DKxanthene. Low production of SM in the wild type bacteria makes searching for production optimization methods highly desirable. Identification and induction of endogenous key molecular feature(s) regulating the production level of the metabolites remain promising, while heterologous expression of the biosynthetic genes is not always efficient because of various complicating factors including codon usage bias. This study established proteomic and molecular approaches to elucidate the regulatory roles of the ROK regulatory protein in the modification of secondary metabolite biosynthesis. Interestingly, the results revealed that rok inactivation significantly reduced the production of the SM and also changed the motility in the bacteria. Electrophoretic mobility shift assay using purified ROK protein indicated a direct enhancement of the promoters encoding transcription of the DKxanthene, myxochelin A, and myxalamide A biosynthesis machinery. Comparative proteomic analysis by two-dimensional fluorescence difference in-gel electrophoresis (2D-DIGE) was employed to identify the protein profiles of the wild type and rok mutant strains during early and late logarithmic growth phases of the bacterial culture. Resulting data demonstrated overall 130 differently altered proteins by the effect of the rok gene mutation, including putative proteins suspected to be involved in transcriptional regulation, carbohydrate metabolism, development, spore formation, and motility. Except for a slight induction seen in the production of myxovirescin A in a rok over-expression background, no changes were found in the formation of the other SM. From the outcome of our investigation, it is possible to conclude that ROK acts as a pleiotropic regulator of secondary metabolite formation and development in M. xanthus, while its direct effects still remain speculative. More experiments are required to elucidate in detail the variable regulation effects of the protein and to explore applicable approaches for generating valuable SM in this bacterium.
    • Data-driven assessment of eQTL mapping methods.

      Michaelson, Jacob J; Alberts, Rudi; Schughart, Klaus; Beyer, Andreas; Cellular Networks and Systems Biology, Biotechnology Center - TU Dresden, Dresden, Germany. (2010)
      The analysis of expression quantitative trait loci (eQTL) is a potentially powerful way to detect transcriptional regulatory relationships at the genomic scale. However, eQTL data sets often go underexploited because legacy QTL methods are used to map the relationship between the expression trait and genotype. Often these methods are inappropriate for complex traits such as gene expression, particularly in the case of epistasis.
    • Deletion of Irf3 and Irf7 Genes in Mice Results in Altered Interferon Pathway Activation and Granulocyte-Dominated Inflammatory Responses to Influenza A Infection.

      Hatesuer, Bastian; Hoang, Hang Thi Thu; Riese, Peggy; Trittel, Stephanie; Gerhauser, Ingo; Elbahesh, Husni; Geffers, Robert; Wilk, Esther; Schughart, Klaus; Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr.7, 38124 Braunschweig, Germany. (2017)
      The interferon (IFN) pathway plays an essential role in the innate immune response following viral infections and subsequent shaping of adaptive immunity. Infections with influenza A viruses (IAV) activate the IFN pathway after the recognition of pathogen-specific molecular patterns by respective pattern recognition receptors. The IFN regulatory factors IRF3 and IRF7 are key players in the regulation of type I and III IFN genes. In this study, we analyzed the role of IRF3 and IRF7 for the host response to IAV infections in Irf3-/-, Irf7-/-, and Irf3-/-Irf7-/- knockout mice. While the absence of IRF3 had only a moderate impact on IFN expression, deletion of IRF7 completely abolished IFNα production after infection. In contrast, lack of both IRF3 and IRF7 resulted in the absence of both IFNα and IFNβ after IAV infection. In addition, IAV infection of double knockout mice resulted in a strong increase of mortality associated with a massive influx of granulocytes in the lung and reduced activation of the adaptive immune response.
    • Detection of anti-HPV11-L1 antibodies in immune sera from patients suffering from recurrent respiratory papillomatosis using ELISA.

      Durzyńska, Julia; Błazejewska, Paulina; Szydłowski, Jarosław; Goździcka-Józefiak, Anna; Department of Molecular Virology, Faculty of Biology, University of A. Mickiewicz, Poznan, Poznan. juliadur@amu.edu.pl (2010-08)
      Infection with human papillomaviruses (mostly HPV6 and HPV11) may lead to recurrent respiratory papillomatosis (RRP), a chronic disease affecting 2-4/100,000 people. Papillomas have to be removed surgically so patients can breathe normally. Papillomas often grow back and some patients are subjected to a number of operations. In general, asymptomatic HPV-positive people have low levels of antiviral antibodies in their sera, as the human humoral response is weak due to HPV's biology. In patients suffering from RRP who have undergone multiple surgeries, a blood-epithelium barrier breach stimulates the production of anti-HPV antibodies. Our study's aim was to produce HisTag-HPV11-L1 major capsid protein in E. coli cells, and to purify it. We also sought to detect anti-HPV11-L1 antibodies in antisera obtained from RRP patients using ELISA. Clinical samples were collected from 47 patients with RRP (antisera and papillomas), and from 32 controls (sera and oral swabs), from the Wielkopolska region of Poland. Antisera and control sera were used to coat microplates, HisTag-HPV11-L1 antigen was applied, and antibody-antigen complexes were detected by anti-HisTag monoclonal antibody in an ELISA assay. Simultaneously, total cellular DNA was extracted from papillomas and oral squamous cells obtained from controls. All DNA samples were screened for HPV DNA using MY-PCR. All patients were HPV-positive (30% for HPV6 and 70% for HPV11). Statistically significant correlations were found between the amount of anti-HPV11-L1 antibodies in the sera of RRP patients and the number of surgical procedures they underwent. Although HPV virus-like particles are most often used for anti-HPV antibody detection, the ELISA method presented herein is another viable option for use in RRP patients.
    • Distinct gene loci control the host response to influenza H1N1 virus infection in a time-dependent manner.

      Nedelko, Tatiana; Kollmus, Heike; Klawonn, Frank; Spijker, Sabine; Lu, Lu; Heßman, Manuela; Alberts, Rudi; Williams, Robert W; Schughart, Klaus; Department of Infection Genetics, Helmholtz Centre for Infection Research and University of Veterinary Medicine Hannover, 38124, Braunschweig, Germany. (2012)
      There is strong but mostly circumstantial evidence that genetic factors modulate the severity of influenza infection in humans. Using genetically diverse but fully inbred strains of mice it has been shown that host sequence variants have a strong influence on the severity of influenza A disease progression. In particular, C57BL/6J, the most widely used mouse strain in biomedical research, is comparatively resistant. In contrast, DBA/2J is highly susceptible.
    • Dynamic gene network reconstruction from gene expression data in mice after influenza A (H1N1) infection.

      Dimitrakopoulou, Konstantina; Tsimpouris, Charalampos; Papadopoulos, George; Pommerenke, Claudia; Wilk, Esther; Sgarbas, Kyriakos N; Schughart, Klaus; Bezerianos, Anastasios; Helmholtz Centre for infection research, Inhoffenstr. 7, D-38124 Braunschweig, Germany. (2011)
      The immune response to viral infection is a temporal process, represented by a dynamic and complex network of gene and protein interactions. Here, we present a reverse engineering strategy aimed at capturing the temporal evolution of the underlying Gene Regulatory Networks (GRN). The proposed approach will be an enabling step towards comprehending the dynamic behavior of gene regulation circuitry and mapping the network structure transitions in response to pathogen stimuli.
    • Eine innovative Mauspopulation als genetisches Modell für den Menschen

      Leist, Sarah; Kollmus, Heike; Pilzner, Carolin; Schughart, Klaus; Infektionsgenetic, Hemholtz Zentrum für Infektionsforschung, Inhoffenstr. 7, 38125Braunschweig (2013-11-21)
    • The endosomal Toll-like receptors 7 and 9 cooperate in detection of MHV68 infection.

      Bussey, Kendra A; Murthy, Sripriya; Reimer, Elisa; Chan, Baca; Hatesuer, Bastian; Schughart, Klaus; Glaunsinger, Britt; Adler, Heiko; Brinkmann, Melanie M; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (Amercan Society of Microbiology, 2018-11-14)
      Murine gammaherpesvirus 68 (MHV68) is an amenable small animal model for study of the human pathogens Epstein-Barr virus and Kaposi’s sarcoma-associated herpesvirus. Here, we have characterized the roles of the endosomal TLR escort protein UNC93B, endosomal TLR7, 9, and 13, and cell surface TLR2 in MHV68 detection. We found that the interferon α (IFNα) response of plasmacytoid dendritic cells (pDC) to MHV68 was reduced in Tlr9-/- cells compared to wildtype (WT), but not completely lost. Tlr7-/- pDC responded similarly to WT. However, we found that in Unc93b-/- pDC, as well as in Tlr7/Tlr9-/- double knockout pDC, the IFNα response to MHV68 was completely abolished. Thus, the only pattern recognition receptors contributing to the IFNα response to MHV68 in pDC are TLR7 and TLR9, but the contribution of TLR7 is masked by the presence of TLR9. To address the role of UNC93B and TLR for MHV68 infection in vivo, we infected mice with MHV68. Lytic replication of MHV68 after intravenous infection was enhanced in the lungs, spleen, and liver of UNC93B-deficient mice, in the spleen of TLR9-deficient mice, and in the liver and spleen of Tlr7/Tlr9-/- mice. The absence of TLR2 or TLR13 did not affect lytic viral titers. We then compared reactivation of MHV68 from latently infected WT, Unc93b-/-, Tlr7/Tlr9-/-, Tlr7-/-, and Tlr9-/- splenocytes. We observed enhanced reactivation and latent viral loads, particularly from Tlr7/Tlr9-/- splenocytes, compared to WT. Our data show that UNC93B- dependent TLR7 and TLR9 cooperate in and contribute to detection and control of MHV68 infection.
    • Equivalence of self- and staff-collected nasal swabs for the detection of viral respiratory pathogens.

      Akmatov, Manas K; Gatzemeier, Anja; Schughart, Klaus; Pessler, Frank; Department of Epidemiology, Helmholtz Centre for Infection Research, Braunschweig, Germany. (2012)
      The need for the timely collection of diagnostic biosamples during symptomatic episodes represents a major obstacle to large-scale studies on acute respiratory infection (ARI) epidemiology. This may be circumvented by having the participants collect their own nasal swabs. We compared self- and staff-collected swabs in terms of swabbing quality and detection of viral respiratory pathogens.
    • Exchange of amino acids in the H1-haemagglutinin to H3 residues is required for efficient influenza A virus replication and pathology in Tmprss2 knock-out mice.

      Lambertz, Ruth L O; Pippel, Jan; Gerhauser, Ingo; Kollmus, Heike; Anhlan, Darisuren; Hrincius, Eike R; Krausze, Joern; Kühn, Nora; Schughart, Klaus; Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2018-09-01)
      The haemagglutinin (HA) of H1N1 and H3N2 influenza A virus (IAV) subtypes has to be activated by host proteases. Previous studies showed that H1N1 virus cannot replicate efficiently in Tmprss2/ knock-out mice whereas H3N2 viruses are able to replicate to the same levels in Tmprss2/ as in wild type (WT) mice. Here, we investigated the sequence requirements for the HA molecule that allow IAV to replicate efficiently in the absence of TMPRSS2. We showed that replacement of the H3 for the H1-loop sequence (amino acids 320 to 329, at the C-terminus of HA1) was not sufficient for equal levels of virus replication or severe pathology in Tmprss2/ knock-out mice compared to WT mice. However, exchange of a distant amino acid from H1 to H3 sequence (E31D) in addition to the HA-loop substitution resulted in virus replication in Tmprss2/ knockout mice that was comparable to WT mice. The higher virus replication and lung damage was associated with increased epithelial damage and higher mortality. Our results provide further evidence and insights into host proteases as a promising target for therapeutic intervention of IAV infections.
    • Gene expression changes in the host response between resistant and susceptible inbred mouse strains after influenza A infection.

      Alberts, Rudi; Srivastava, Barkha; Wu, Haiya; Viegas, Nuno; Geffers, Robert; Klawonn, Frank; Novoselova, Natalia; do Valle, Tania Zaverucha; Panthier, Jean-Jacques; Schughart, Klaus; et al. (2010-04)
      Inbred mouse strains exhibit differences in susceptibility to influenza A infections. However, the molecular mechanisms underlying these differences are unknown. Therefore, we infected a highly susceptible mouse strain (DBA/2J) and a resistant strain (C57BL/6J) with influenza A H1N1 (PR8) and performed genome-wide expression analysis. We found genes expressed in lung epithelium that were specifically down-regulated in DBA/2J mice, whereas a cluster of genes on chromosome 3 was only down-regulated in C57BL/6J. In both mouse strains, chemokines, cytokines and interferon-response genes were up-regulated, indicating that the main innate immune defense pathways were activated. However, many immune response genes were up-regulated in DBA/2J much stronger than in C57BL/6J, and several immune response genes were exclusively regulated in DBA/2J. Thus, susceptible DBA/2J mice showed a hyper-inflammatory response. This response is similar to infections with highly pathogenic influenza virus and may serve as a paradigm for a hyper-inflammatory host response to influenza A virus.
    • Genetically diverse CC-founder mouse strains replicate the human influenza gene expression signature.

      Elbahesh, Husni; Schughart, Klaus; Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2016-05-19)
      Influenza A viruses (IAV) are zoonotic pathogens that pose a major threat to human and animal health. Influenza virus disease severity is influenced by viral virulence factors as well as individual differences in host response. We analyzed gene expression changes in the blood of infected mice using a previously defined set of signature genes that was derived from changes in the blood transcriptome of IAV-infected human volunteers. We found that the human signature was reproduced well in the founder strains of the Collaborative Cross (CC) mice, thus demonstrating the relevance and importance of mouse experimental model systems for studying human influenza disease.