Team:OhioState/Implementation

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Implementation

Implementation

Our proposed end users are patients who are suffering from sepsis. With the phage therapy, the genetically engineered phage will be intravenously injected into the patients, serving as a treatment for sepsis. It will insert its genome into the cell and be incorporated into the host cell. As a result, the desired protein will then be made and influence the lipid-A molecules in the cell membrane, to avoid cytokine storms and treat sepsis. In addition, we developed a phage database with all the necessary information about the phages that can infect sepsis-related bacteria. We envision others, who are doing research on sepsis and phage therapy, being able to easily find needed information through Phage Database.



Next Step - Further Wetlab Research

After getting positive results from the lab, we can continue on with animal trials. Animal models of phage therapy are a critical approach to verify the efficiency of the phage therapy in vivo and search for potential adverse effects1. However, there are several challenges of the animal trials. The amount of liquid volume is limited for animals, such as mice, especially when the liquid is administered intravenously or intranasally. As a result, the concentration of the phage needs to accommodate. Also, because of the effects of the laboratory environment and other variables during the trials, the animal experiments may fail to ensure the reliability of administration on humans. The species differences in physiology and genetics between humans and animals can explain the unreliability and limitations of the animal trials as well2. Besides, there is one possibility that our fully developed phages continue to replicate and infect E.coli strains outside of the source of sepsis for a patient. This could lead to complications down the line for the patient after the threat of sepsis. This could be possibly mitigated by mutating certain genes that are involved in the lytic cycle.



Next Step - Phage Therapy

In the long run, we plan to have phage therapy on sepsis approved by the FDA and start on human trials. Also the phage database we created can be updated as more phages or information are discovered. To implement phage therapy on patients diagnosed with sepsis, the first step is to determine the type of phage that is going to be used in the phage therapy. Since phages only infect specific bacteria strain, it’s critical to find the specific phage that can infect the sepsis-causing bacteria for the patient. Our phage database plays a critical role at this step. By going through the phage list, instead of reviewing all the literature, doctors and researchers can save a lot of time to find the phage right for different patients. A list of potential phages would be helpful in case that some of them don’t work as planned in the following steps. Next, multiple anti-lipid A proteins and their pathways will be researched into. The proteins can be either binding to lipid A or altering the structures of lipid A in order to neutralize lipid A. The lipid-A neutralizing proteins will be inserted into the chosen phage. After successful insertion of the anti-lipid A proteins, the phage with the protein will be mass produced for administration. There are several companies commercializing bacteriophages or phage-based products for therapeutic purposes. However, an effective, constant and controllable process has yet to be developed. The processes in the laboratories are well defined but they’re difficult to scale up. Because of the biological nature of the system and the diverse types of interactions that occur between phages and bacteria, there are still many challenges along the way and further studies on it are needed3. Then delivery of the therapeutic phages between labs and hospitals is also critical. Dry formulations of embedded phage are one of the approaches to store bacteriophages for long-term. The drying of phages formulations can be achieved through ambient air drying, spray drying, lyophilization or spray freeze-drying4. After the engineered phages arrive at the hospitals, they can be intravenously administered into the patient to treat sepsis. It can be done orally, locally or by applying drops of phage suspension to the eye, middle ear or nasal mucosa. At the same time, the etiologic agents are monitored for phage susceptibility. The treatment can be 1 to 16 weeks and can be applied for up to 14 days after negative cultures are obtained5.

Figure 1. Proposed Phage Therapy Implementation


Phage Database


x


Phage Name Locus Genome (bp) GC% Linear/Circular DNA Lytic/Lysogenic Date Genome
PT1028 NC_007045 15,603 31.40 linear 12/20/2020 https://www.ncbi.nlm.nih.gov/nuccore/NC_007045.1
66 AY954949 18,199 29.30 linear 4/15/2005 https://www.ncbi.nlm.nih.gov/nuccore/AY954949
44AHJD NC_004678 16,784 29.70 linear lytic 12/20/2020 https://www.ncbi.nlm.nih.gov/nuccore/29565721
P68 18,221 29.30 lytic
187 AY954950 39,620 34.30 linear lytic 4/15/2005 https://www.ncbi.nlm.nih.gov/nuccore/AY954950
69 AY954951 42,732 34.30 linear 4/15/2005 https://www.ncbi.nlm.nih.gov/nuccore/AY954951
53 AY954952 43,883 34.10 linear 4/15/2005 https://www.ncbi.nlm.nih.gov/nuccore/AY954952
85 AY954953 44,283 34.60 linear 4/15/2005 https://www.ncbi.nlm.nih.gov/nuccore/AY954953
2638A AY954954 41,318 36.90 linear lytic 4/15/2005 https://www.ncbi.nlm.nih.gov/nuccore/AY954954
77 NC_005356 41,708 33.50 linear 12/20/2020 https://www.ncbi.nlm.nih.gov/nuccore/41189515
42e AY954955 45,861 33.70 linear 4/15/2005 https://www.ncbi.nlm.nih.gov/nuccore/AY954955
3A AY954956 43,095 33.50 linear 4/15/2005 https://www.ncbi.nlm.nih.gov/nuccore/AY954956
47 AY954957 44,777 33.50 linear 4/15/2005 https://www.ncbi.nlm.nih.gov/nuccore/AY954957
37 AY954958 43,681 35.10 linear 4/15/2005 https://www.ncbi.nlm.nih.gov/nuccore/AY954958
EW AY954959 45,286 38.00 linear 4/15/2005 https://www.ncbi.nlm.nih.gov/nuccore/AY954959
96 AY954960 43,576 35.00 linear 4/15/2005 https://www.ncbi.nlm.nih.gov/nuccore/AY954960
ROSA AY954961 43155 35.10 linear 4/15/2005 https://www.ncbi.nlm.nih.gov/nuccore/AY954961
71 AY954962 43,114 35.20 linear 4/15/2005 https://www.ncbi.nlm.nih.gov/nuccore/AY954962
55 AY954963 41,902 35.70 linear 4/15/2005 https://www.ncbi.nlm.nih.gov/nuccore/AY954963
29 AY954964 42,802 35.40 linear 4/15/2005 https://www.ncbi.nlm.nih.gov/nuccore/AY954964
52A AY954965 41,690 35.50 linear 4/15/2005 https://www.ncbi.nlm.nih.gov/nuccore/AY954965
88 AY954966 43,231 35.50 linear 4/15/2005 https://www.ncbi.nlm.nih.gov/nuccore/AY954966
92 AY954967 42,431 35.70 linear 4/15/2005 https://www.ncbi.nlm.nih.gov/nuccore/AY954967
X2 AY954968 43,440 36.00 linear 4/15/2005 https://www.ncbi.nlm.nih.gov/nuccore/AY954968
K NC_005880 148,317 30.60 linear lytic 12/20/2020 https://www.ncbi.nlm.nih.gov/nuccore/NC_005880.2
G1 NC_007066 138,715 30.40 linear lytic 4/15/2005 https://www.ncbi.nlm.nih.gov/nuccore/NC_007066.1
Twort NC_007021 130,706 30.30 linear lytic 4/15/2005 https://www.ncbi.nlm.nih.gov/nuccore/NC_007021.1
JD007 NC_019726 141,836 30.37 circular 12/21/2020 https://www.ncbi.nlm.nih.gov/nuccore/NC_019726.1
vB_SauM_Remus NC_022090 134,643 29.97 linear 12/21/2020 https://www.ncbi.nlm.nih.gov/nuccore/NC_022090.1
vB_SauM_Romulus NC_020877 131,332 30.01 linear 12/21/2020 https://www.ncbi.nlm.nih.gov/nuccore/NC_020877.1
MSA6 JX080304 148,243 30.24 linear 3/31/2014 https://www.ncbi.nlm.nih.gov/nuccore/JX080304.2
B1 MG656408 148,884 30.25 linear lytic 4/27/2018 https://www.ncbi.nlm.nih.gov/nuccore/1327516593
JA1 MF405094 147,135 30.25 linear 4/27/2018 https://www.ncbi.nlm.nih.gov/nuccore/1227560290
Staph1N JX080300 145,647 30.41 linear 3/28/2014 https://www.ncbi.nlm.nih.gov/nuccore/JX080300.2
A5W EU418428 145,542 30.42 linear 3/12/2014 https://www.ncbi.nlm.nih.gov/nuccore/EU418428.2
Fi200W JX080303 148,481 30.39 linear 3/28/2014 https://www.ncbi.nlm.nih.gov/nuccore/JX080303.2
676Z JX080302 148,564 30.41 linear 3/26/2020 https://www.ncbi.nlm.nih.gov/nuccore/JX080302.2
P4W JX080305 147,590 30.39 linear 3/28/2014 https://www.ncbi.nlm.nih.gov/nuccore/JX080305.2
A3R JX080301 141,018 30.50 linear 3/26/2020 https://www.ncbi.nlm.nih.gov/nuccore/JX080301.2
812 NC_029080 142,096 30.40 linear 12/20/2020 https://www.ncbi.nlm.nih.gov/nuccore/985759046
IME-SA1 KP687431 140,218 30.33 circular 4/15/2015 https://www.ncbi.nlm.nih.gov/nuccore/KP687431.1
IME-SA2 KP687432 140,906 30.33 circular 4/15/2015 https://www.ncbi.nlm.nih.gov/nuccore/KP687432.1
IME-SA118 KR902361 139,750 30.32 linear 7/15/2015 https://www.ncbi.nlm.nih.gov/nuccore/KR902361.1
IME-SA119 KR908644 141,028 30.33 linear 7/15/2015 https://www.ncbi.nlm.nih.gov/nuccore/KR908644.1
Team1 NC_025417 140,903 30.33 linear 12/21/2020 https://www.ncbi.nlm.nih.gov/nuccore/NC_025417.1
SA5 JX875065 137,031 30.42 linear 12/7/2012 https://www.ncbi.nlm.nih.gov/nuccore/JX875065.1
GH15 NC_019448 139,806 30.23 linear 12/20/2020 https://www.ncbi.nlm.nih.gov/nuccore/NC_019448.1
ISP FR852584 138,339 30.42 linear 9/19/2011 https://www.ncbi.nlm.nih.gov/nuccore/FR852584.1
MCE-2014 NC_025416 141,907 30.38 linear 12/21/2020 https://www.ncbi.nlm.nih.gov/nuccore/NC_025416.1
P108 NC_025426 140,807 30.22 linear 12/21/2020 https://www.ncbi.nlm.nih.gov/nuccore/NC_025426.1
phiP68 NC_004679 18,227 29.32 linear 12/20/2020 https://www.ncbi.nlm.nih.gov/nuccore/29565743
philPLA-C1C NC_028962 140,961 27.96 linear 12/21/2020 https://www.ncbi.nlm.nih.gov/nuccore/NC_028962.1
philPLA-RODI NC_028765 142,348 30.42 linear 12/21/2020 https://www.ncbi.nlm.nih.gov/nuccore/NC_028765.1
phiSA012 NC_023573 142,094 30.31 linear lytic 12/21/2020 https://www.ncbi.nlm.nih.gov/nuccore/NC_023573.1
S25-3 NC_022920 139,738 30.22 circular 12/20/2020 https://www.ncbi.nlm.nih.gov/nuccore/NC_022920.1
S25-4 NC_022918 132,123 30.31 circular 12/20/2020 https://www.ncbi.nlm.nih.gov/nuccore/NC_022918.1
Sb-1 NC_023009 127,188 30.48 linear lytic 12/20/2020 https://www.ncbi.nlm.nih.gov/nuccore/NC_023009.1
Stau2 KP881332 133,798 29.97 linear lytic 5/26/2016 https://www.ncbi.nlm.nih.gov/nuccore/KP881332.1
phiPVL NC_002321 41,401 33.55 linear 6/7/2021 https://www.ncbi.nlm.nih.gov/nuccore/NC_002321.1
phiSLT AB045978 42,942 33.31 linear 6/26/2008 https://www.ncbi.nlm.nih.gov/nuccore/AB045978.2
phiPV83-pro NC_002486 45,636 33.48 linear 12/20/2020 https://www.ncbi.nlm.nih.gov/nuccore/NC_002486.1
108-PVL 44,107
Sa2mw 45,924
Sa2958 46,046
Sa2usa 43,062
phi7247PVL NC_048624 42,481 33.31 linear 12/20/2020 https://www.ncbi.nlm.nih.gov/nuccore/NC_048624.1
phi5967PVL NC_019921 42,146 33.31 linear 12/20/2020 https://www.ncbi.nlm.nih.gov/nuccore/NC_019921.1
phiETA NC_003288 43,081 35.43 circular 12/20/2020 https://www.ncbi.nlm.nih.gov/nuccore/NC_003288.1
phiN315 NC_004740 44,082 32.78 linear 6/29/2020 https://www.ncbi.nlm.nih.gov/nuccore/NC_004740.1
Mu50A 43,053
Mu50B 44,391
Sa3mw lytic
Sa3ms 42,612 lysogenic
Sa3 (OC8) LC129040 42,984 33.09 linear 10/19/2016 https://www.ncbi.nlm.nih.gov/nuccore/LC129040.1
phi 11 AF424781 43,604 34.50 linear lytic 01/06/2020 https://www.ncbi.nlm.nih.gov/nuccore/AF424781.1
phi 12 AF424782 44,970 33.35 linear 06/10/2020 https://www.ncbi.nlm.nih.gov/nuccore/AF424782.1
13 42,774
L54a temperate
phiNM1 NC_008583 43,128 34.16 linear 10/12/2021 https://www.ncbi.nlm.nih.gov/nuccore/NC_008583.1
phiNM2 NC_028913 43,145 34.59 linear temperate 10/12/2021 https://www.ncbi.nlm.nih.gov/nuccore/NC_028913.1
phiNM3 NC_008617 44,061 32.99 linear 10/12/2021 https://www.ncbi.nlm.nih.gov/nuccore/NC_008617.1
phiNM4 NC_028864 43,189 34.74 linear 10/12/2021 https://www.ncbi.nlm.nih.gov/nuccore/NC_028864.1
80 42,140
80alpha NC_009526 43,864 34.10 linear 10/11/2021 https://www.ncbi.nlm.nih.gov/nuccore/NC_009526.1
phiMR11 NC_010147 43,011 35.63 linear 10/12/2021 https://www.ncbi.nlm.nih.gov/nuccore/NC_010147.1
phiMR25 NC_010808 44,342 34.33 linear lysogenic 10/12/2021 https://www.ncbi.nlm.nih.gov/nuccore/NC_010808.1
phiSauS-IPLA88 NC_011614 42,526 34.91 linear 10/12/2021 https://www.ncbi.nlm.nih.gov/nuccore/NC_011614.1
phiSauS-IPLA35 NC_011612 45,344 33.25 linear 10/12/2021 https://www.ncbi.nlm.nih.gov/nuccore/NC_011612.1
TEM126 NC_054978 41,882 33.68 linear temperate 10/12/2021 https://www.ncbi.nlm.nih.gov/nuccore/NC_054978.1
SA11 NC_019511 136,326 30.04 linear lytic 10/12/2021 https://www.ncbi.nlm.nih.gov/nuccore/NC_019511.1
SAP2 17,938
vB_SauH_SAP1 MT786458 143,375 30.16 linear 08/24/2020 https://www.ncbi.nlm.nih.gov/nuccore/MT786458.1
SAP3 MT724048 41,949 35.35 linear 08/03/2020 https://www.ncbi.nlm.nih.gov/nuccore/MT724048.1
SK311 141,100
SA039 AP018375 141,038 30.38 linear 02/28/2018 https://www.ncbi.nlm.nih.gov/nuccore/AP018375.1

x

Phage Name Locus Genome (bp) GC% Linear/Circular DNA Lytic/Lysogenic Date Genome
SOCP KJ617393 19,347 38.82 linear Lytic 2/25/2015 https://www.ncbi.nlm.nih.gov/nuccore/KJ617393
Dp-1 HQ268735 56,506 40.34 linear Lytic 7/25/2016 https://www.ncbi.nlm.nih.gov/nuccore/HQ268735.1/
Cp-1 NC_001825 19,343 38.83 linear Lytic 12/20/2020 https://www.ncbi.nlm.nih.gov/nuccore/NC_001825
HB-3 linear Temperate https://www.ncbi.nlm.nih.gov/nuccore/215055
EJ-1 NC_005294 42,935 39.64 linear Temperate 12/20/2020 https://www.ncbi.nlm.nih.gov/nuccore/NC_005294.1
Dp-4
Cp-7 NC_042114 19,741 39.19 linear 12/20/2020 https://www.ncbi.nlm.nih.gov/nuccore/NC_042114.1
Cp-9 linear
MM1-1998 DQ113772 38,893 38.16 circular Temperate 7/24/2006 https://www.ncbi.nlm.nih.gov/nuccore/DQ113772.1
MM1 NC_003050 40,248 38.46 linear Temperate 12/20/2020 https://www.ncbi.nlm.nih.gov/nuccore/NC_003050.2
MS1 KY629621 56,075 42.26 linear Lytic 5/11/2017 https://www.ncbi.nlm.nih.gov/nuccore/KY629621
MS2 NC_001417 3,569 Linear RNA 6/4/2019 https://www.ncbi.nlm.nih.gov/nuccore/NC_001417.2
ϕX174

x

Phage Name Locus Genome (bp) GC% Linear/Circular DNA Lytic/Lysogenic Date Genome
T4 NC_000866 168,903 35.30 linear lytic 01/23/2021 https://www.ncbi.nlm.nih.gov/nuccore/NC_000866.4
lambda NC_001416 48,502 49.86 linear temperate 12/20/2020 https://www.ncbi.nlm.nih.gov/nuccore/NC_001416.1
HK620 AF335538 38,297 46.69 circular 4/23/2002 https://www.ncbi.nlm.nih.gov/nuccore/AF335538.1
T5 AY543070 121,750 39.27 linear lytic 4/19/2004 https://www.ncbi.nlm.nih.gov/nuccore/AY543070.1
Goslar
PTXU04
vB_EcoM_KWBSE43-6 NC_048186 158,607 46.09 linear 12/21/2020 https://www.ncbi.nlm.nih.gov/nuccore/NC_048186.1
JLK-2012 NC_049942 57,198 50.72 linear 12/21/2020 https://www.ncbi.nlm.nih.gov/nuccore/NC_049942.1
Rac-SA53
vB_EcoM_G17 MK327931 370,817 34.33 linear 3/25/2019 https://www.ncbi.nlm.nih.gov/nuccore/MK327931.1
vB_EcoM_Schickermooser NC_048196 151,194 39.01 linear 12/21/2020 https://www.ncbi.nlm.nih.gov/nuccore/NC_048196.1
EdH4 MK327930 136,031 43.65 linear 3/25/2019 https://www.ncbi.nlm.nih.gov/nuccore/MK327930.1
teqsoen MN895436 166,468 35.47 linear 02/01/2021 https://www.ncbi.nlm.nih.gov/nuccore/MN895436.1
teqdroes NC_054932 166,833 35.44 linear 6/8/2021 https://www.ncbi.nlm.nih.gov/nuccore/NC_054932.1
teqhal MN895435 168,070 35.45 linear 02/01/2021 https://www.ncbi.nlm.nih.gov/nuccore/MN895435.1
teqskov NC_054934 165,017 35.36 linear 6/8/2021 https://www.ncbi.nlm.nih.gov/nuccore/NC_054934.1
vB_EcoM_WFC NC_048195 72472 46.01 linear 12/21/2020 https://www.ncbi.nlm.nih.gov/nuccore/NC_048195.1
vB_EcoM_AYO145A NC_028825 87,372 39.00 linear 12/21/2020 https://www.ncbi.nlm.nih.gov/nuccore/NC_028825.1
teqhad NC_054933 167,892 35.33 linear 6/8/2021 https://www.ncbi.nlm.nih.gov/nuccore/NC_054933.1
moskry MN850651 169,410 37.64 linaer 2/1/2021 https://www.ncbi.nlm.nih.gov/nuccore/MN850651.1
vB_EcoS_HdH2 NC_048748 120,120 39.32 linear 12/21/2020 https://www.ncbi.nlm.nih.gov/nuccore/NC_048748.1
mogra MN850579 168,724 37.69 linear 2/1/2021 https://www.ncbi.nlm.nih.gov/nuccore/MN850579.1
mobilu MN850622 163,063 37.68 linear 2/1/2021 https://www.ncbi.nlm.nih.gov/nuccore/MN850622.1

x

Phage Name Locus Genome (bp) GC% Linear/Circular DNA Lytic/Lysogenic Date Genome
StB12 NC_020490 44,714 34.17 linear 10/21/2021 https://www.ncbi.nlm.nih.gov/nuccore/NC_020490.2
StB27 NC_019914 40,071 33.22 linear 10/21/2021 https://www.ncbi.nlm.nih.gov/nuccore/NC_019914.1
StB20 NC_019915 40,917 34.07 linear 10/21/2021 https://www.ncbi.nlm.nih.gov/nuccore/NC_019915.1
118II
phi29 NC_011048 19,282 39.99 linear 10/11/2021 https://www.ncbi.nlm.nih.gov/nuccore/NC_011048.1
phi68
95
127
171A
207
113
113A
188
112
108
phi187



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