Anaplasma phagocytophilum Transmission Activates Immune Pathways While Repressing Wound Healing in the Skin
Abstract
:1. Introduction
2. Materials and Methods
2.1. Anaplasma Phagocytophilum Culture
2.2. Mice Infections
2.3. Tick Infestations
2.4. RNA-Seq and Pathway Analysis of Skin Biopsies
2.5. qRT-PCR of Skin Biopsies
3. Results
3.1. Tick Feeding Induces the Expression of Neutrophil Chemotaxis and Inflammatory Responses in the Skin
3.2. Anaplasma Phagocytophilum Transmission Induces the Upregulation of Interferon Signaling Genes
3.3. Differentially Expressed Genes (DEGs) Stimulated during Tick Feeding and A. Phagocytophilum Transmission
3.4. Confirmation of Th1 Cytokines Upregulation and Downregulation of ECM Genes by qRT-PCR
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Primer Name | Primer Sequence | Ta * | Product Size (bp) | Reference |
---|---|---|---|---|
Mactin F | 5′-ACGCAGAGGGAAATCGTCCGTGAC-3′ | 60 °C | 101 | [24] |
Mactin R | 5′-ACGCGGGAGGAAGAGGATGCGGCAGTG-3′ | 60 °C | ||
Actin Is F | 5′-GGTCATCACAATCGGCAA-3′ | 54 °C | 108 | [25] |
Actin Is R | 5′-ATGGAGTTGTACGTGGTCTC-3′ | 54 °C | ||
P44 F | 5′-ATGGAAGGTAGTGTTGGTTATGGTATT-3′ | 56 °C | 77 | [26] |
P44 R | 5′-TTGGTCTTGAAGCGCTCGTA-3′ | 56 °C | ||
16s rRNA F | 5′-GGTGAGTAATGCATAGGAATC-3′ | 53 °C | 108 | [27] |
16s rRNA R | 5′-GCTCATCTAATAGCGATAAATC-3′ | 53 °C | ||
rpoB F | 5′-CTTTATCCTGCTTTAGAACAACATC-3′ | 52 °C | 286 | [18] |
rpoB R | 5′-GGTCCGTATGGTCTGGTTACT-3′ | 52 °C | ||
Ifng F | 5′-AGCGTCATTGAATCACACCT-3′ | 54 °C | 196 | This study |
Ifng R | 5′-ATCAGCAGCGACTCCTTTTC-3′ | 54 °C | ||
IL1βF | 5′-CCTGTGTAATGAAAGACGGC-3′ | 54 °C | 216 | This study |
IL1βR | 5′-TGTCCTGACCACTGTTGTTT-3′ | 54 °C | ||
Irf1 F | 5′-ATAACTCCAGCACTGTCACC-3′ | 54 °C | 177 | This study |
IrF1 R | 5′-AAGGTCTTCGGCTATCTTCC-3′ | 54 °C | ||
Stat2 F | 5′- TGGGACTTCGGCTTCTTGAC-3′ | 57 °C | 247 | This study |
Stat2 R | 5′- TCTTGGGATTTGGGCTGAGC-3′ | 57 °C | ||
S100a8 F | 5′-CACCATGCCCTCTACAAGAA-3′ | 54 °C | 161 | This study |
S100a8 R | 5′-CCCACTTTTATCACCATCGC-3′ | 54 °C | ||
Acan F | 5′-CAGATGGCACCCTCCGATAC-3′ | 57 °C | 151 | This study |
Acan R | 5′-GACACACCTCGGAAGCAGAA-3′ | 57 °C | ||
Matn3 F | 5′-GAGGGTGGCTGTGGTGAACT-3′ | 59 °C | 160 | This study |
Matn3 R | 5′-GGCTTCCTCCATCGCTGTCT-3′ | 59 °C |
Comparison | Upregulated Genes | Downregulated Genes | Total Significantly DEGs |
---|---|---|---|
Intact skin v uninfected tick bite sites | 797 | 416 | 1213 |
Intact skin v Anaplasma-infected tick bite | 1417 | 1142 | 2559 |
Uninfected tick bite sites v Anaplasma-infected tick bite | 476 | 146 | 622 |
Pathway Identifier | Pathway Name | Number Entities Found | Number Entities Total | Entities p-Value | Entities FDR |
---|---|---|---|---|---|
R-HSA-909733 | Interferon alpha/beta signaling | 50 | 188 | 1.11 × 10−16 | 1.52 × 10−14 |
R-HSA-6783783 | Interleukin-10 signaling | 38 | 86 | 1.11 × 10−16 | 1.52 × 10−14 |
R-HSA-913531 | Interferon signaling | 81 | 394 | 1.11 × 10−16 | 1.52 × 10−14 |
R-HSA-1280215 | Cytokine signaling in immune system | 149 | 1092 | 1.11 × 10−16 | 1.52 × 10−14 |
R-HSA-168256 | Immune system | 213 | 2684 | 1.11 × 10−16 | 1.52 × 10−14 |
R-HSA-449147 | Signaling by interleukins | 70 | 643 | 4.66 × 10−15 | 5.32 × 10−13 |
R-HSA-877300 | Interferon gamma signaling | 41 | 250 | 1.18 × 10−14 | 1.15 × 10−12 |
R-HSA-380108 | Chemokine receptors bind chemokines | 17 | 57 | 1.40 × 10−10 | 1.21 × 10−8 |
R-HSA-6785807 | Interleukin-4 and interleukin-13 signaling | 26 | 211 | 2.48 × 10−7 | 1.88 × 10−5 |
R-HSA-1169410 | Antiviral mechanism by IFN-stimulated genes | 14 | 94 | 1.97 × 10−5 | 0.001342146 |
R-HSA-375276 | Peptide ligand-binding receptors | 20 | 203 | 1.29 × 10−4 | 0.007973888 |
R-HSA-1169408 | ISG15 antiviral mechanism | 11 | 83 | 3.99 × 10−4 | 0.022716167 |
R-HSA-9705462 | Inactivation of CSF3 (G-CSF) signaling | 6 | 27 | 6.44 × 10−4 | 0.03349729 |
Pathway Identifier | Pathway Name | Number Entities Found | Number Entities Total | Entities p-Value | Entities FDR |
---|---|---|---|---|---|
R-HSA-1474244 | Extracellular matrix organization | 29 | 329 | 1.11 × 10−16 | 3.26 × 10−14 |
R-HSA-2022090 | Assembly of collagen fibrils and other multimeric structures | 13 | 67 | 7.42 × 10−13 | 5.98 × 10−11 |
R-HSA-1474290 | Collagen formation | 15 | 104 | 8.05 × 10−13 | 5.98 × 10−11 |
R-HSA-1474228 | Degradation of the extracellular matrix | 17 | 148 | 8.20 × 10−13 | 5.98 × 10−11 |
R-HSA-8948216 | Collagen chain trimerization | 11 | 44 | 3.13 × 10−12 | 1.72 × 10−10 |
R-HSA-1650814 | Collagen biosynthesis and modifying enzymes | 13 | 76 | 3.52 × 10−12 | 1.72 × 10−10 |
R-HSA-3000178 | 13 | 79 | 5.66 × 10−12 | 2.38 × 10−10 | |
R-HSA-216083 | Integrin cell surface interactions | 11 | 86 | 3.39 × 10−9 | 1.22 × 10−7 |
R-HSA-1442490 | Collagen degradation | 10 | 69 | 5.56 × 10−9 | 1.78 × 10−7 |
R-HSA-419037 | NCAM1 interactions | 6 | 44 | 9.59 × 10−6 | 2.78 × 10−4 |
R-HSA-1566948 | Elastic fiber formation | 6 | 46 | 1.23 × 10−5 | 3.20 × 10−4 |
R-HSA-8874081 | MET activates PTK2 signaling | 5 | 32 | 2.86 × 10−5 | 6.86 × 10−4 |
R-HSA-3000171 | Non-integrin membrane-ECM interactions | 6 | 61 | 5.86 × 10−5 | 0.001289879 |
R-HSA-375165 | NCAM signaling for neurite outgrowth | 6 | 70 | 1.24 × 10−4 | 0.002108039 |
R-HSA-186797 | Signaling by PDGF | 6 | 70 | 1.24 × 10−4 | 0.002108039 |
R-HSA-3656244 | Defective B4GALT1 causes B4GALT1-CDG (CDG-2d) | 3 | 9 | 1.38 × 10−4 | 0.002108039 |
R-HSA-3656225 | Defective CHST6 causes MCDC1 | 3 | 9 | 1.38 × 10−4 | 0.002108039 |
R-HSA-3656243 | Defective ST3GAL3 causes MCT12 and EIEE15 | 3 | 9 | 1.38 × 10−4 | 0.002108039 |
R-HSA-8875878 | MET promotes cell motility | 5 | 45 | 1.41 × 10−4 | 0.002108039 |
R-HSA-2022854 | Keratan sulfate biosynthesis | 4 | 37 | 7.38 × 10−4 | 0.010327613 |
R-HSA-2129379 | Molecules associated with elastic fibers | 4 | 38 | 8.14 × 10−4 | 0.011395335 |
R-HSA-2022857 | Keratan sulfate degradation | 3 | 22 | 0.001819501 | 0.023653508 |
R-HSA-2243919 | Crosslinking of collagen fibrils | 3 | 24 | 0.002325531 | 0.027906369 |
R-HSA-1638074 | Keratan sulfate/keratin metabolism | 4 | 52 | 0.002542129 | 0.029455221 |
R-HSA-399710 | Activation of AMPA receptors | 2 | 7 | 0.002677747 | 0.029455221 |
R-HSA-6806834 | Signaling by MET | 5 | 88 | 0.002781469 | 0.03059616 |
R-HSA-1369062 | ABC transporters in lipid homeostasis | 3 | 29 | 0.00394569 | 0.039456898 |
R-HSA-8951671 | RUNX3 regulates YAP1-mediated transcription | 2 | 9 | 0.004364679 | 0.043646794 |
Pathway Identifier | Pathway Name | Number Entities Found | Number Entities Total | Entities p-Value | Entities FDR |
---|---|---|---|---|---|
R-HSA-6783783 | Interleukin-10 signaling | 36 | 86 | 7.12 × 10−14 | 1.17 × 10−10 |
R-HSA-6798695 | Neutrophil degranulation | 61 | 480 | 4.41 × 10−13 | 3.62 × 10−10 |
R-HSA-380108 | Chemokine receptors bind chemokines | 24 | 57 | 7.27 × 10−11 | 3.97 × 10−8 |
R-HSA-6785807 | Interleukin-4 and interleukin-13 signaling | 42 | 211 | 2.18 × 10−8 | 8.94 × 10−6 |
R-HSA-2500257 | Resolution of sister chromatid cohesion | 28 | 134 | 4.57 × 10−7 | 1.50 × 10−4 |
R-HSA-2467813 | Separation of sister chromatids | 27 | 195 | 1.10 × 10−6 | 3.00 × 10−4 |
R-HSA-141424 | Amplification of signal from the kinetochores | 22 | 94 | 7.82 × 10−6 | 0.001602622 |
R-HSA-141444 | Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal | 22 | 94 | 7.82 × 10−6 | 0.001602622 |
R-HSA-5663220 | RHO GTPases activate formins | 24 | 149 | 1.20 × 10−5 | 0.002177163 |
R-HSA-68877 | Mitotic prometaphase | 31 | 211 | 1.79 × 10−5 | 0.002933421 |
R-HSA-9648025 | EML4 and NUDC in mitotic spindle formation | 24 | 121 | 3.02 × 10−5 | 0.004498095 |
R-HSA-69618 | Mitotic spindle checkpoint | 22 | 111 | 1.34 × 10−4 | 0.018203955 |
Pathway Identifier | Pathway Name | Number Entities Found | Number Entities Total | Entities p-Value | Entities FDR |
---|---|---|---|---|---|
R-HSA-400253 | Circadian clock | 9 | 105 | 0.001723 | 0.60096047 |
R-HSA-5682910 | LGI-ADAM interactions | 3 | 14 | 0.005775 | 0.60096047 |
R-HSA-3000480 | Scavenging by Class A receptors | 5 | 49 | 0.008965 | 0.60096047 |
R-HSA-8874081 | MET activates PTK2 signaling | 4 | 32 | 0.009601 | 0.60096047 |
R-HSA-3000178 | ECM proteoglycans | 6 | 79 | 0.016775 | 0.60096047 |
R-HSA-2022870 | Chondroitin sulfate biosynthesis | 3 | 25 | 0.026832 | 0.60096047 |
R-HSA-1482922 | Acyl chain remodeling of PI | 3 | 25 | 0.026832 | 0.60096047 |
R-HSA-391903 | Eicosanoid ligand-binding receptors | 3 | 25 | 0.026832 | 0.60096047 |
R-HSA-8949275 | RUNX3 regulates immune response and cell migration | 2 | 10 | 0.02741 | 0.60096047 |
R-HSA-8875878 | MET promotes cell motility | 4 | 45 | 0.029135 | 0.60096047 |
R-HSA-1482925 | Acyl chain remodeling of PG | 3 | 26 | 0.029633 | 0.60096047 |
R-HSA-1442490 | Collagen degradation | 5 | 69 | 0.033148 | 0.60096047 |
R-HSA-430116 | GP1b-IX-V activation signaling | 2 | 12 | 0.038188 | 0.60096047 |
R-HSA-3000170 | Syndecan interactions | 3 | 29 | 0.038924 | 0.60096047 |
R-HSA-1482801 | Acyl chain remodeling of PS | 3 | 31 | 0.045843 | 0.60096047 |
R-HSA-6785807 | Interleukin-4 and interleukin-13 signaling | 10 | 211 | 0.046493 | 0.60096047 |
R-HSA-1650814 | Collagen biosynthesis and modifying enzymes | 5 | 76 | 0.046724 | 0.60096047 |
R-HSA-391908 | Prostanoid ligand receptors | 2 | 14 | 0.050296 | 0.60096047 |
R-HSA-2214320 | Anchoring fibril formation | 2 | 15 | 0.0568 | 0.60096047 |
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Underwood, J.; Harvey, C.; Lohstroh, E.; Pierce, B.; Chambers, C.; Guzman Valencia, S.; Oliva Chávez, A.S. Anaplasma phagocytophilum Transmission Activates Immune Pathways While Repressing Wound Healing in the Skin. Life 2022, 12, 1965. https://doi.org/10.3390/life12121965
Underwood J, Harvey C, Lohstroh E, Pierce B, Chambers C, Guzman Valencia S, Oliva Chávez AS. Anaplasma phagocytophilum Transmission Activates Immune Pathways While Repressing Wound Healing in the Skin. Life. 2022; 12(12):1965. https://doi.org/10.3390/life12121965
Chicago/Turabian StyleUnderwood, Jacob, Cristina Harvey, Elizabeth Lohstroh, Branden Pierce, Cross Chambers, Stephanie Guzman Valencia, and Adela S. Oliva Chávez. 2022. "Anaplasma phagocytophilum Transmission Activates Immune Pathways While Repressing Wound Healing in the Skin" Life 12, no. 12: 1965. https://doi.org/10.3390/life12121965