Progress 07/01/16 to 06/30/21
Outputs
Target Audience:Researchers in the field of veterinary immunology, infectious disease and medicine. Ultimate goal of this project is to develop new low cost, effective treatments for cattle and other livestock diseases, thus livestock producers represent the long term targetted audience. Changes/Problems:
Nothing Reported
What opportunities for training and professional development has the project provided?B. abortus is a Select Agent, so critical to this project was meeting the CDCD Select Agent requirements for annual training and professional development for all personnel, including the PI. that work with the organism. How have the results been disseminated to communities of interest?Through publication and research meeting presentations. What do you plan to do during the next reporting period to accomplish the goals?
Nothing Reported
Impacts
What was accomplished under these goals?
The majority of the Hatch funding for this project supported a portion of the salary of the PI. Progress under objectives #1 and #2 was reported in 2020 and most of the goals were accomplished. We did continue our study of the effect of the TLR4/liposome agonists on macrophage killing of Brucella abortus in vitro and clearance of the bacterium in vivo. These studies are ongoing and also contribute to efforts under objective 3, and a manuscript was submitted in 2021. Ongoing experiments are focused on addressing reviewers comments. Per objective #3, we continued other work on B. abortus as reported in previous years, which focused on studies of host innate immune responses against the bacterium and testing of bacteriophages as novel countermeasures against infection. We continued work on a NIH R21 grant that was funded in support of these B. abortus studies. As a part of these experiments, we isolated a unique phage for B. abortus from the environment. Sequence analysis of the new phage was reported in a manuscript in 2020. Efficacy experiments were done in the past year in vitro and in vivo on different phage preparations. We found that less phage is better as a treatment and when high doses of phage are used in vitro or in vivo, reduced clearance of B. abortus was seen. The high dose phage treatments induced a suppressed macrophage response in these experiments. A manuscript is in preparation, which focuses on these studies. As introduced last year, a new project on Mycoplasma ovipneumoniae (M. ovi) in domestic sheep was started, which is also focused on the innate immune response against this pathogen and the identification of lytic bacteriophage. A USDA/NIFA Seed grant was funded in 2019 to support efforts in this new project. We have succeed in identifying the first phage of M. ovi which are currently being characterized. As part of these efforts, we worked with another research group in the department in establishing a flock of sheep free of M. ovi for use in challenge studies and tested antibiotic clearance of experimental infection by M. ovi in these animals. New in the last 1.5 years of this project was development and submission of a new multi-state USDA/NIFA project on COVID-19. Research has just started on studies of host responses against SARS-CoV-2, which includes studies of both innate and adaptive immune responses. Four papers were published in this area in 2021. Finally, a 5 year renewal proposal of this Hatch project was developed, reviewed and approved in Spring 2021, with the new interation starting 7/1/21
Publications
- Type:
Journal Articles
Status:
Published
Year Published:
2021
Citation:
Hedges, J.F., Thompson, M.A., Snyder, D.T., Robison, A., Taylor, M.P., and Jutila MA. 2021. Titers, prevalence, and duration of SARS-CoV-2 antibodies in a local COVID-19 outbreak and following vaccination. Vaccines (Basel). 9(6):587.
- Type:
Journal Articles
Status:
Published
Year Published:
2021
Citation:
Santiago-Frangos A., Hall, L.N., Nemudraia, A., Nemudryi, A., Krishna, P., Wiegand, T., Wilkinson, R.A., Snyder, D.T., Hedges, J.F., Cicha, C., Lee, H.H., Graham, A., Jutila, M.A., Taylor, M.P., and Wiedenheft, B. 2021. Intrinsic signal amplification by type III CRISPR-Cas systems provides a sequence-specific SARS-CoV-2 diagnostic. Cell Rep Med. 2(6):100319.
- Type:
Journal Articles
Status:
Published
Year Published:
2021
Citation:
Nemudryi, A., Nemudraia, A., Wiegand, T., Nichols, J., Snyder, D.T., Hedges, J.F., Cicha, C., Lee, H., Vanderwood, K.K., Bimczok, D., Jutila, M.A., and Wiedenheft, B. 2021. SARS-CoV-2 genomic surveillance identifies naturally occurring truncation of ORF7a that limits immune suppression. Cell Rep. 35(9):109197
- Type:
Journal Articles
Status:
Published
Year Published:
2021
Citation:
Loveday, E.K., Hain, K.S., Kochetkova, I., Hedges, J.F., Robison, A., Snyder. D.T., Brumfield, S.K., Young, M.J., Jutila, M.A., Chang, C.B., and Taylor, M.P. 2021. Effect of inactivation methods on SARS-CoV-2 virion protein and structure. Viruses. 13(4):562.
- Type:
Conference Papers and Presentations
Status:
Published
Year Published:
2021
Citation:
Hedges, J.F., Thompson, M., Snyder, D.T., Robison, A., Taylor, M. , Jutila, M., IMMUNOLOGY2021, "Titers, prevalence and duration of SARS-CoV-2 antibodies in two waves of a local COVID-19 outbreak", American Association of Immunologists, Remote. (May 2021).
- Type:
Journal Articles
Status:
Submitted
Year Published:
2021
Citation:
Johnson, T., Jones, K., Jacobson, B.T., Schearer, J., Jutila, M.A., Rynda-Apple, A., Besser, T., and Bimczok, D. Experimental infection of specific-pathogen-free domestic lambs with Mycoplasma ovipneumoniae causes asymptomatic colonization of the upper airways that is resistant to antibiotic treatment. Submitted.
- Type:
Journal Articles
Status:
Submitted
Year Published:
2021
Citation:
Hedges, J.F., Snyder, D.T., Robison, A., Thompson, M., Aspelin, K., Baldridge, J., and Jutila, M.A. 2021. TLR4 agonist liposome formulation effectively stimulates innate immunity and enhances protection from Brucella abortus infection. Submitted.
|
Progress 10/01/19 to 09/30/20
Outputs
Target Audience:Researchers in the field of veterinary immunology, infectious disease and medicine. Ultimate goal is to develop new low cost, effective treatments for cattle and other livestock diseases, thus livestock producers represent the long term targetted audience. Changes/Problems:The main challenge in the past year was associated with the COVID-19 crisis in 2020, which hindered progress on a number of our projects, particularly in the Spring. What opportunities for training and professional development has the project provided?As part of working with Select Agents, all lab personnel, including the PI, participated in required annual trainings on operation procedures, and safety and security protocols required to work with such pathogens. These efforts contribute to the professional development of all lab personnel and are critical to the CDC certified MSU Select Agent program. How have the results been disseminated to communities of interest?Our main approach in the past year was through submission of primary research papers and abstracts/presentations at national meetings. What do you plan to do during the next reporting period to accomplish the goals?Per our planned research efforts, we will continue work on each of the objectives in our funded projects, as defined above. We hope to complete testing of novel TLR4 synthetic agonists in potentially countering naturally acquired scours causing infectious agents. We will continue to expand efforts in studies of B. abortus under objective #3, specifically studies on the innate immune response and the use of bacteriophage as countermeasures against infection. These studies are funded by an NIH R21 grant. As also mentioned above, we will focus new efforts on M.ovipneumoniae infection in domestic sheep through a new USDA/NIFA Seed grant award. Finally, as menitoned earlier, new for 2020 was submission of a new multi-state USDA/NIFA project on COVID-19. In vivo infection studies, with a focus on both innate and adative immune responses associated will be a primary focus in the coming year.
Impacts
What was accomplished under these goals?
The majority of the Hatch funding for this project supported a portion of the salary of the PI. Work under all three objectives continued in the past year. Under objectives #1 and #2 we continued our analysis of novel TLR4 agonists, which effectively activate bovine gamma/delta T cells. TLR4 agonists were used to treat neonatal calves as a broad spectrum treatment for naturally acquired scours. Use of amphotericin B, which was studied in an early USDA/NIFA funded project, led to reduced incidence of scours in our previous experiments. In a follow-up experiment using synthetic TLR4 agonists in liposomes, we tested whether treatment might lead to accelerated weight gain in the calves. Unfortunately, the first formulation tested had no effect. We expanded our study of the effect of the TLR4/liposome agonists on macrophage killing of Brucella abortus in vitro and clearance of the bacterium in vivo. These studies are ongoing and contribute to efforts under objective 3, and a manuscript is in preparation. Specifically, under objective #3, we continued other work on B. abortus as reported last year, which focused on studies of host innate immune responses against the bacterium and testing of bacteriophages as novel countermeasures against infection. A new NIH R21 grant was funded in support of these B. abortus studies. As a part of these experiments, we isolated a unique phage for B. abortus from the environment. Sequence analysis of the new phage was reported in a manuscript in 2020. Efficacy experiments were done in the past year in vitro and in vivo on different phage preparations. We found that less phage is better as a treatment and when high doses of phage are used in vitro or in vivo, reduced clearance of B. abortus was seen. The high dose phage treatments induced a suppressed macrophage response in these experiments. A manuscript is in preparation, which focuses on these studies. As introduced last year, a new project on Mycoplasma ovipneumoniae (M. ovi) in domestic sheep was started, which is also focused on the innate immune response against this pathogen and the identification of lytic bacteriophage. A USDA/NIFA Seed grant was funded in 2019 to support efforts in this new project. As part of these efforts, we worked with another research group in the department in establishing a flock of sheep free of M. ovi for use in challenge studies. Finally, new in the latter half of this funded year was development and submission of a new multi-state USDA/NIFA project on COVID-19. Research has just started on studies of host responses against SARS-CoV-2, which includes studies of both innate and adaptive immune responses.
Publications
- Type:
Journal Articles
Status:
Published
Year Published:
2020
Citation:
Cicha C, Hedges J, Novak I, Snyder D, Jutila M, Wiedenheft B. 2020. Complete genome sequence of the Brucella abortus phage EF4, determined using long-read sequencing. Micobiol. Resour. Announc. 9:e00212-20.
- Type:
Conference Papers and Presentations
Status:
Accepted
Year Published:
2020
Citation:
Isolation of potential therapeutic, lytic bacteriophage for Mycoplasma ovipneumoniae (M. ovi). Jodi Hedges, Klara Aspilin,Macy Thompson, Kerri Jones, Tom Besser, and Mark Jutila CRWAD 2020.
- Type:
Conference Papers and Presentations
Status:
Accepted
Year Published:
2020
Citation:
Establishment of a Mycoplasma ovipneumoniae-free sheep herd by supervised lambing and artificial rearing. TheaSherwood, Kerri Jones, Agnieszka Rynda-Apple, Thomas Besser, Mark Jutila, Diane Bimczok. CRWAD 2020
|
Progress 10/01/18 to 09/30/19
Outputs
Target Audience:Researchers in the field of veterinary immunology, infectious disease and medicine. Ultimate goal is to develop new low cost, effective treatments for cattle and other livestock diseases, thus livestock producers represent the long term targetted audience. Changes/Problems:
Nothing Reported
What opportunities for training and professional development has the project provided?As part of working with Select Agents, all lab personnel, including the PI, particiapted in required annual trainings on operation procedures, and safety and security protocols required to work with such infectious agents. These efforts contribute to the professional development of all lab personnel and are critical to the CDC certified MSU Select Agent program. How have the results been disseminated to communities of interest?Our main approach in the past year was through submission of primary research papers and book chapters, and presentations at national meetings. What do you plan to do during the next reporting period to accomplish the goals?Per our planned research efforts, we will continue work on each of the objectives in our funded projects, as defined above. New funding has just been received to expand our in vivo studies of TLR4 agonists in newborn calves. We will be testing the effects of these agonists in countering naturally acquired scours causing infectious agents. We will continue to expand efforts in B. abortus under objective #3, specifically studies on the innate immune response and the use of bacteriophage as countermeasures against infection funded by a new NIH R21 grant. As also mentioned above, we will focus new efforts on M. ovipneumoniae infection in domestic sheep through a new USDA/NIFA Seed grant award.
Impacts
What was accomplished under these goals?
The majority of the Hatch funding for this project supported a portion of the salary of the PI. Work under all three objectives continued in the past year. Under objectives #1 and #2 we continued our analysis of novel synthetic TLR4 agonists, which effectively activate bovine gamma/delta T cells. Different formulations continued to be tested, including, as reported last year, a liposomal preparation, in in vitro assays and in a Salmonella challenge model in calves. In vitro assays in the past year focused on testing if the preparation increased macrophage killing of Salmonella. We compared effects of the preparation on macrophage killing of Brucella abortus, as well. Under objective #3, we continued our work on Coxeilla burnetii and continued new studies on Brucella abortus as reported last year. Both efforts focused on studies of host innate immune responses against these Select Agents. Using a novel transgenic mouse that expresses human TLR4 we have shown that human TLR4 is permissive to C. burnetii infection. TLR4 expression on epithelial cells appears to account for this phenotype (paper published in 2019). We also expanded studies on B. abortus and showed that TLR4 agonists enhance innate immune responses against the bacteria. We also started testing the use of bacteriophage as countermeasures against B. abortus infection. A new NIH R21 grant was funded for these new B. abortus studies. Finally, a new project on Mycoplasma ovipneumoniae in domestic sheep was started, which is also focused on the innate immune response against this pathogen and the identification of lytic bacteriophage. A USDA/NIFA Seed grant was funded to support efforts in this new project.
Publications
- Type:
Journal Articles
Status:
Published
Year Published:
2019
Citation:
Lei B, Minor D, Feng W, Jerome M, Quinn MT, Jutila MA, Liu M. 2019. Tissue Tropism in Streptococcal Infection: Wild-Type M1T1 Group A Streptococcus is efficiently cleared by neutrophils using an NADPH oxidase-dependent mechanism in the lung but not in the skin. Infect Immun. 87(10). pii: e00527-19.
- Type:
Journal Articles
Status:
Published
Year Published:
2019
Citation:
Robison A, Snyder DT, Christensen K, Kimmel E, Hajjar AM, Jutila MA, Hedges JF. 2019. Expression of human TLR4/myeloid differentiation factor 2 directs an early innate immune response associated with modest increases in bacterial burden during Coxiella burnetii infection. Innate Immun. 25(7):401-411.
- Type:
Book Chapters
Status:
Published
Year Published:
2019
Citation:
Hedges, J.F and Jutila.A.A. 2019. Harnessing gd T cells as natural immune modulators. In "Mucosal Vaccines." Kiyono,H. and Pascual, D.W. editors. Elsevier.
|
Progress 10/01/17 to 09/30/18
Outputs
Target Audience:Researchers in the field of veterinary immunology, infectious disease and medicine. Ultimate goal is to develop new low cost effective treatments for cattle diseases, thus livestock producers represent the long term targetted audience. Changes/Problems:
Nothing Reported
What opportunities for training and professional development has the project provided?
Nothing Reported
How have the results been disseminated to communities of interest?Our main apporach in the past year was through submission of primary research papers and book chapters. What do you plan to do during the next reporting period to accomplish the goals?Per our planned research efforts, we will continue work on each of the objectives in our funded project as defined above. Specifically, using new funding that is in place we will expand efforts in B. abortus under objective #3, specifically studies on the innate immune response and the use of bacteriophage as countermeasures against infection. We plan on pursuing additional preliminary in vivo studies on immune modulators in bovine calves under objective #2. Per the latter, we will continue to examine lipid preparations of the synthetic TLR4 agonists in our Salmonella enteritis model in calves, since they appear to have the most robust in vivo activity, in the absence of overt toxicity. As also mentioned above, we plan on studying M. ovipneumoniae in domestic sheep if new funding is forthcoming.
Impacts
What was accomplished under these goals?
The majority of the Hatch funding for this project supported a portion of the salary of the PI. Work under all three objectives continued in the past year. Under objectives #1 and #2 we continued our analysis of novel synthetic TLR4 agonists, which effectively activate bovine gamma/delta T cells. Different formulations were tested, including a liposomal preparation. Interestingly, the liposomal preparation, which shows far less toxicity in vivo, activated gamma/delta T cells, but not monocytes in invitro assays. We also continued testing these materials in a Salmonella enteritis model in bovine calves. This work contributed to a USDA SBIR grant submission and also a provisional patent application. Under objective #3, we continued our work on Coxeilla burnetii and included new studies on Brucella abortus. Both efforts focused on studies of host innate immune responses against these Select Agents. Using a novel transgenic mouse that expresses human TLR4 we have shown that human TLR4 is permissive to C. burnetii infection. TLR4 expression on epithelial cells appears to account for this phenotype (paper submitted). We submitted an NIH grant for funding to expand on these observtions, which was not funded. Since that time, we have generated preliminary evidence that the microbiome may be involved in the permissive response in human TLR4 expressing mice. This is now a focus of our ongoing studies on C. burnetii. We also expanded studies on B. abortus and showed that TLR4 agonists enhance innate immune responses against the bacteria. We also started testing the use of bacteriophage as countermeasures against B. abortus infection. Two NIH grants were submitted for these new studies. Finally, a new project on Mycoplasma ovipneumoniae in domestic sheep was started, which is also focused on the innate immune response against this pathogen and the identifcation of lytic bacteriophage. A grant to the USDS/NIFA/AFRI program was submitted for this work.
Publications
- Type:
Journal Articles
Status:
Published
Year Published:
2017
Citation:
Snyder, D.T., Hedges, J.F., and Jutila, M.A. 2017. Getting inside type I IFNs: type I IFNs in intracellular bacterial infections. J. Immunol. Res. 2017:9361802. PMCID: PMC5424489
- Type:
Book Chapters
Status:
Accepted
Year Published:
2019
Citation:
Harnessing gd T cells as Natural Immune Modulators
Jodi F. Hedges and Mark A. Jutila. In "Mucosal Vaccines: Innovation for Preventing Infectious Diseases, 2e", Elsevier
- Type:
Journal Articles
Status:
Under Review
Year Published:
2019
Citation:
Amanda Robison; Deann T Snyder; Kelly Christensen; Emily Kimmel; Adeline M Hajjar; Mark A Jutila;Jodi Hedges. 2018. Expression of human TLR4/MD-2 directs an early innate immune response associated with modest increased bacterial burden in Coxiella burnetii infection. Under review
|
Progress 10/01/16 to 09/30/17
Outputs
Target Audience:Researchers in the field of veterinary immunology, infectious disease and medicine. Ultimate goal is to develop new cost effective treatments for cattle diseases, thus livestock producers represent the long term targetted audience. Changes/Problems:
Nothing Reported
What opportunities for training and professional development has the project provided?
Nothing Reported
How have the results been disseminated to communities of interest?Our main apporach in the past year was through submission of primary research papers and reviews. We have submitted a comprehensive paper on the role of human TLR4 in C. burnetii infection. We also published a paper on the role of type I IFNs in intracellular bacterial infections. Some of our work was also presented at the Annual USDA/NIFA/AFRI PI's meeting in Chicago in 2016. What do you plan to do during the next reporting period to accomplish the goals?A major effort for the coming year is to acquire new, competitive grants to fund work under all three objectives. We plan on submitting to both the NIH and USDA for funding. Per our planned research efforts, we will continue work on each of the objectives in our funded projects. Specifically, using funding that is in place we will continue our characterization of the role of human TLR4 in C. burnetii infection under objective #3 and as described in previous progress reports, and we will pursue additional preliminary in vivo studies in bovine calves under objective #2. Per the latter, we intend to focus on lipid preparations of the synthetic TLR4 agonists in our Salmonella enteritis model in calves, since they appear to have the most robust in vivo activity, in the absence of overt toxicity.
Impacts
What was accomplished under these goals?
Work under all three objectives continued in the past year. Under objectives #1 and #2 we determined the in vitro activity of novel synthetic TLR4 agonists, which effectively activate bovine gamma/delta T cells, similar to other agonists, such as amphotericin B and various plant polysaccharides described in previous progress reports. The main readout in our invitro assays is specific upregulation of the IL-2 receptor on gamma/delta T cells, as measured by flow cytometry. Cytokine responses are also measured. We are now testing these materials in a Salmonella enteritis model in bovine calves. This work has contributed to a USDA SBIR submission focused on the commercial development of TLR4 agonists for use in treating bovine scours. Under objective #3, we continued our work on Coxeilla burnetii and included new studies on Brucella abortus, both focused on studies of host innate immune responses. Using a novel transgenic mouse that expresses human TLR4 we have shown that human TLR4 is permissive to C. burnetii infection. TLR4 expression on epithelial cells accounts for this phenotype. A new grant was submitted to the NIH to define the molecular basis for this novel phenotype. We have also expanded our studies of the role of type I IFNs in the C. burnetii infection model and have collaborated on studies of these cyokines in a Clostridium difficle model.
Publications
- Type:
Journal Articles
Status:
Published
Year Published:
2017
Citation:
Snyder, DT, Hedges, J.F., and Jutila, M.A. 2017. Getting Inside type I IFNS: Type I interferons in intracellular bacterial infections. J. Immunol. Res. In press.
- Type:
Journal Articles
Status:
Submitted
Year Published:
2018
Citation:
Robison, A., Kimmel,E., Snyder, D., Christensen, K., Hajjar, A.M., Jutila, M.A., and Hedges, J.F. 2017. Expression of human TLR4/MD-2 in the non-hematopoietic compartment promotes infection with Coxiella burnetii in vivo. Submitted.
|
Progress 07/01/16 to 09/30/16
Outputs
Target Audience:Researchers in the field of veterinary immunology, infectious disease and medicine. Changes/Problems:
Nothing Reported
What opportunities for training and professional development has the project provided?
Nothing Reported
How have the results been disseminated to communities of interest?Results of this project were pubished in 4 peer-reviewed journals and three abstracts were presented at a scientific meeting. What do you plan to do during the next reporting period to accomplish the goals?We plan to continue our grant funded projects in the coming year. Specifically, our focus for 2017 will be on testing of synthetic TLR agonists in our bovine calf scours model and continuing studies of innate immune responses in C. burnetii infection. Per the former, we will continue in vitro and initiate in vivo testing of novel synthetic TLR agonists. Per the latter, we plan on expanding on our initial finding that human TLR4 is more permissive to C. burnetii infection than mouse TLR4 by determining if TLR4 expression on macrophages (cell type infected) is most important or whether expression on other cell types, such as epithelial cells, is involved. We also will expand on studies of the role of type I IFNs in C. burnetii infection.
Impacts
What was accomplished under these goals?
We made progress on all funded projects in the laboratory. Specifically, per Objectives 1 and 2, we have initiatied testing of various TLR agonists in vitro and in vivo to identify novel materials that might be marketable as novel immunemodulators to enhance calf resistance to scouring agents. We have shown that the bacterial procuct amphotericin B and the plant product AcaiPS are potent immunemodulators and effectively activated innate immune cells in bovine calves. Amphotericin B also enhances resistance to Salmonella challenge. Mechanism of action studies show that these materials function through TLR pathways. We have now initiated studies testing various synthetic TLR agonists that may serve as even better "drugable" materials. Per Objective 3, we have continued our studies of innate immune responses against C. burnetii infection. We have define roles for TLR2, TLR4 and MyD88 in the early innate immune response and have found that human TLR4 "senses" the pathogen differently than mouse TLR4, actually leading to enhance disease. This Hatch project, which primarily supports the institutional salary of the PI, supported 4 peer-reviewed publications in 2016 and 3 abstracts at a national scientific meeting (American Association of Immunologists).
Publications
- Type:
Journal Articles
Status:
Published
Year Published:
2016
Citation:
Ramstead, A., Robison, A., Blackwell, A., Jerome. M., Freedman, B., Lubick, K., Hedges, J., and Jutila, M. 2016. Role of TLR2, TLR4, and MyD88 during pulmonary Coxiella burnetii infection. Infection and Immunity 84: 940-949.
- Type:
Journal Articles
Status:
Published
Year Published:
2016
Citation:
Schepetkin, I.A., Ramstead, A.G., Kirpotina, L.N., Voyich, J.M., Jutila, M.A., and Quinn, M.T. 2016. Therapeutic potential of polyphenols from Epilobium angustifolium (Firewee). Phytother. Res. 30: 1287-1297.
- Type:
Journal Articles
Status:
Published
Year Published:
2016
Citation:
Hedges, J.F., Holderness, J., and Jutila, M.A. 2016. Adjuvant materials that enhance bovine ?? T cell responses. Vet Immunol Immunopathol. (16): 30-38.
- Type:
Journal Articles
Status:
Published
Year Published:
2016
Citation:
Hedges JF, Robison A, Kimmel E, Christensen K, Lucas E, Ramstead A, Jutila MA. 2016. Type I interferons counters or promotes Coxiella burnetii replication dependent on tissue. Infection and Immunty. 24: 1815-1825.
|
|