Co-infections alter the host immune response but how the systemic and local processes at the site of infection interact is still unclear. The majority of studies on co-infections concentrate on one of the infecting species, an immune function or group of cells and often focus on the initial phase of the infection. Here, we used a combination of experiments and mathematical modelling to investigate the network of immune responses against single and co-infections with the respiratory bacterium Bordetella bronchiseptica and the gastrointestinal helminth Trichostrongylus retortaeformis. Our goal was to identify representative mediators and functions that could capture the essence of the host immune response as a whole, and to assess how their relative contribution dynamically changed over time and between single and co-infected individuals. Network-based discrete dynamic models of single infections were built using current knowledge of bacterial and helminth immunology; the two single infection models were combined into a co-infection model that was then verified by our empirical findings. Simulations showed that a T helper cell mediated antibody and neutrophil response led to phagocytosis and clearance of B. bronchiseptica from the lungs. This was consistent in single and co-infection with no significant delay induced by the helminth. In contrast, T. retortaeformis intensity decreased faster when co-infected with the bacterium. Simulations suggested that the robust recruitment of neutrophils in the co-infection, added to the activation of IgG and eosinophil driven reduction of larvae, which also played an important role in single infection, contributed to this fast clearance. Perturbation analysis of the models, through the knockout of individual nodes (immune cells), identified the cells critical to parasite persistence and clearance both in single and co-infections. Our integrated approach captured the within-host immuno-dynamics of bacteria-helminth infection and identified key components that can be crucial for explaining individual variability between single and co-infections in natural populations. Helikar Tomas thelika@unmc.edu University of Nebraska - Lincoln 2013-06-16T11:27:50Z 2017-07-17T17:04:27Z

<span lang="EN-GB">T. retortaeformis</span><span lang="EN-GB"> Larvae (mouse)</span>

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Activated phagocytes

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T helper cells\r\nsubtype I in systemic compartment<div>For more info: http://www.ncbi.nlm.nih.gov/mesh/68006377</div>

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<span lang="EN-GB">T\r\nhelper cells subtype I in systemic compartment for Bacterium in co-infection (mouse):</span><div>http://www.ncbi.nlm.nih.gov/mesh/68006377<font face="Times New Roman, serif"><br/></font><div style="font-style: normal; font-variant: normal; font-weight: normal; font-family: Arial, Verdana; font-size: 10pt; line-height: normal;"><span lang="EN-GB" style="font-size:12.0pt;line-height:\r\n115%;font-family:"Times New Roman","serif";mso-fareast-font-family:"Times New Roman";\r\nmso-ansi-language:EN-GB;mso-fareast-language:EN-US;mso-bidi-language:AR-SA"> </span></div></div>

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<span lang="EN-GB">Interleukin\r\n12 in systemic compartment (mouse)</span>

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<span lang="EN-GB">T\r\nregulatory cells in lungs/small intestine (mouse):</span><div><span lang="EN-GB">http://www.ncbi.nlm.nih.gov/mesh/68050378</span></div>

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<span lang="EN-GB">Th2\r\ncells in lungs/small intestine for Bacterium pathway in co-infection (mouse):</span><div><span lang="EN-GB">http://www.ncbi.nlm.nih.gov/mesh/68006377</span></div>

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<p style="margin: 0.4em 0px 0.5em;"><span id="parentSpecies:viewSpeciesDescription"><span lang="EN-GB">Recruited neutrophils for Bacterium pathway in co-infection (mouse):</span></span></p><div><span lang="EN-GB">http://www.ncbi.nlm.nih.gov/mesh/68009504</span></div>

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Antibody A for B. bronchiseptica for co-infection (mouse)

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<p style="margin: 0.4em 0px 0.5em;"><span id="parentSpecies:viewSpeciesDescription"><span lang="EN-GB">Dendritic cells in lungs/small intestine for T. retortaeformis pathway in co-infection (mouse):</span></span></p><div><span lang="EN-GB">http://www.ncbi.nlm.nih.gov/mesh/68003713</span></div>

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<font face="Arial, Verdana" size="2">B Cells for Bacterium in co-infection (mouse):</font><div><font face="Arial, Verdana" size="2">http://www.ncbi.nlm.nih.gov/mesh/68001402</font></div>

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<span lang="EN-GB">Epithelial\r\ncells lungs/intestine (mouse) in the T. retortaeformis infection. For more info:</span><div><span lang="EN-GB">http://www.ncbi.nlm.nih.gov/mesh/68004847</span></div>

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<span lang="EN-GB">Interferon\r\ngamma in lungs/small intestine for Bacterium pathway in the co-infection (mouse):</span><div><span lang="EN-GB">http://www.ncbi.nlm.nih.gov/mesh/68007371</span></div>

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<span lang="EN-GB">Th2\r\ncells in lungs/small intestine in T Retortaeformis pathway in co-infection</span><div><span lang="EN-GB">For more information: http://www.ncbi.nlm.nih.gov/mesh/68018418</span></div>

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respiratory bacterium Bordetella bronchiseptica 

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Antigen Antibody complexes in Bacterium pathway of co-infection (mouse)<div>for more information: http://www.ncbi.nlm.nih.gov/mesh/?term=antigen+antibody+complex</div>

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Type three secretion system in the lungs (mouse)

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<span lang="EN-GB">recruited\r\neosinophils (mouse) for more info:</span><div><span lang="EN-GB">http://www.ncbi.nlm.nih.gov/mesh/68004804</span></div>

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<span lang="EN-GB">Th2\r\ncells in systemic compartment in T Retortaeformis pathway in co-infection</span><div><span lang="EN-GB">For more info: http://www.ncbi.nlm.nih.gov/mesh/68018418</span></div>

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<span lang="EN-GB">Dendritic cells in systemic compartment for T. retortaeformis pathway in co-infection (mouse):</span><div><span lang="EN-GB">http://www.ncbi.nlm.nih.gov/mesh/68003713</span></div>

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<span lang="EN-GB">T\r\nhelper cells subtype I in lungs/small intestine for T Retortaeformis pathway in coinfection.</span><div><span lang="EN-GB">For more info: http://www.ncbi.nlm.nih.gov/mesh/68006377</span></div>

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Naive T cells (mouse)

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<span lang="EN-GB">Interleukin\r\n10 in lungs/small intestine (mouse)</span><div><span lang="EN-GB">UniProt AccessionID: </span><a href="http://www.uniprot.org/uniprot/P18893" style="font-size: small; text-decoration: none; font-family: sans-serif; background-color: rgb(255, 255, 255);">P18893</a></div>

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<span style="font-family: arial, sans-serif; font-size: 10pt; font-style: normal; font-variant: normal; font-weight: normal; line-height: 18.0049991607666px; color: rgb(51, 51, 51); background-color: rgb(255, 255, 255);">Interferon gamma in systemic compartment (mouse) more info:</span><div><span style="background-color: rgb(255, 255, 255); line-height: 18.0049991607666px;"><font color="#333333" face="arial, sans-serif" size="2">http://www.ncbi.nlm.nih.gov/mesh/68007371</font></span></div>

2015-12-19T22:52:44Z

<span lang="EN-GB">Interleukin\r\n13 (mouse)</span><div><span lang="EN-GB">UniProt AccessionID: </span><a href="http://www.uniprot.org/uniprot/P20109" style="text-decoration: none; font-family: sans-serif; font-size: small; background-color: rgb(255, 255, 255);">P20109</a></div>

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<span lang="EN-GB">total\r\neosinophils (mouse) for more info:</span><div><span lang="EN-GB">http://www.ncbi.nlm.nih.gov/mesh/68004804</span></div>

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Pro-inflammatory cytokines (mouse) for more info:<div>http://www.ncbi.nlm.nih.gov/mesh/68016207</div>

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Antibody G (mouse)

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<font face="Arial, Verdana" size="2">B Cells in the T. retortaeformis pathway of co-infection (mouse):</font><div><font face="Arial, Verdana" size="2">http://www.ncbi.nlm.nih.gov/mesh/68001402</font></div>

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Complement node in Bacterium pathway of co-infection (mouse)

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<p style="margin: 0.4em 0px 0.5em;"><span id="parentSpecies:viewSpeciesDescription">Macrophages in the lungs for Bacterium pathway in co-infection (mouse):</span></p><div>http://www.ncbi.nlm.nih.gov/mesh/68008264</div>

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<span lang="EN-GB">resident\r\neosinophils (mouse) for more info:</span><div><span lang="EN-GB">http://www.ncbi.nlm.nih.gov/mesh/68004804</span></div>

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<span lang="EN-GB">T. retortaeformis- a gastrointestinal helmith (mouse)</span>

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Interleukin 5 (mouse)<div>UniProt AccessionID: <a href="http://www.uniprot.org/uniprot/P04401" style="font-size: small; text-decoration: none; font-family: sans-serif; background-color: rgb(255, 255, 255);">P04401</a></div>

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<font face="Arial, Verdana" size="2">O-antigen (mouse) for more info:</font><div><font face="Arial, Verdana" size="2">http://www.ncbi.nlm.nih.gov/mesh/68019081</font></div>

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Total neutrophils (mouse):<div>http://www.ncbi.nlm.nih.gov/mesh/68009504</div>

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Antibody E (mouse)

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<span lang="EN-GB">T\r\nregulatory cells in systemic compartment (mouse) for more info:</span><div><span lang="EN-GB">http://www.ncbi.nlm.nih.gov/mesh/68050378</span></div>

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<span lang="EN-GB">Th2\r\ncells in systemic compartment for Bacterium pathway in co-infection (mouse):</span><div><span lang="EN-GB">http://www.ncbi.nlm.nih.gov/mesh/68006377</span></div>

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Interleukin 4 in the small intestines/lungs (mouse)<div>UniProt AccessionID: <a href="http://www.uniprot.org/uniprot/P07750" style="font-size: small; text-decoration: none; font-family: sans-serif; background-color: rgb(255, 255, 255);">P07750</a></div>

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<span lang="EN-GB">Type\r\nthree secretion system in systemic compartment (mouse)</span>

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<span lang="EN-GB">Interleukin\r\n4 in systemic compartment (mouse)</span><div><span lang="EN-GB">UniProt AccessionID: </span><a href="http://www.uniprot.org/uniprot/P07750" style="text-decoration: none; font-family: sans-serif; font-size: small; background-color: rgb(255, 255, 255);">P07750</a></div>

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Referred to as DNE (dead neutrophils) in Thakar et. al paper

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<p style="orphans: 3; widows: 3; line-height: 1.5em; margin: 0.4em 0px 0.5em; color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; background-color: rgb(255, 255, 255);"><span id="parentSpecies:viewSpeciesDescription"><span lang="EN-GB">Recruited neutrophils for T. Retortaeformis pathway in co-infection (mouse):</span></span></p><div style="font-size: 12px; color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255);"><span lang="EN-GB">http://www.ncbi.nlm.nih.gov/mesh/68009504</span></div>

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Represents pH<div><br/></div><div>Phagocytosis (mouse) in coninfection for more info:</div><div>http://www.ncbi.nlm.nih.gov/mesh/68010587</div><div><hr/></div><div><br/></div><div>PH protein in the Drosophila segmentation model (2013)</div>

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<p style="margin: 0.4em 0px 0.5em;"><span id="parentSpecies:viewSpeciesDescription"><span lang="EN-GB">Epithelial cells lungs/intestine (mouse) in the B. Bronchiseptica<span style="orphans: auto; widows: auto;"> </span>infection. For more info:</span></span></p><div><span lang="EN-GB">http://www.ncbi.nlm.nih.gov/mesh/68004847</span></div>

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<font face="Arial, Verdana" size="2">Antibody A for T. Retortaeformis pathway in co-infection (mouse):</font><div><font face="Arial, Verdana" size="2"><br/></font><div style="font-family: Arial, Verdana; font-size: 10pt; font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;">Composed of 2 IGH chains:</div><div><font face="Arial, Verdana" size="2">http://www.ncbi.nlm.nih.gov/gene/3492</font></div></div><div><font face="Arial, Verdana" size="2"><br/></font></div><div><font face="Arial, Verdana" size="2">4 IGL chains:</font></div><div><font face="Arial, Verdana" size="2">http://www.ncbi.nlm.nih.gov/gene/3535</font></div><div><font face="Arial, Verdana" size="2"><br/></font></div><div><font face="Arial, Verdana" size="2">1 IGJ chain:</font></div><div><font face="Arial, Verdana" size="2">http://www.ncbi.nlm.nih.gov/gene/3512</font></div>

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Interferon gamma in lungs/small intestine (mouse)

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<span lang="EN-GB">T\r\nhelper cells subtype I in lungs/small intestine for co-infection (mouse):</span><div><span lang="EN-GB">http://www.ncbi.nlm.nih.gov/mesh/68006377</span></div>

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Antibody G in Bacterium pathway of Co-infection<div>For more info: http://www.ncbi.nlm.nih.gov/mesh/68007074</div>

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<span lang="EN-GB">Dendritic\r\ncells in lungs/small intestine for Bacterium pathway in co-infection (mouse):</span><div><span lang="EN-GB">http://www.ncbi.nlm.nih.gov/mesh/68003713</span></div>

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<span lang="EN-GB">Dendritic\r\ncells in systemic compartment for Bacterium pathway in co-infection (mouse):</span><div><span lang="EN-GB">http://www.ncbi.nlm.nih.gov/mesh/68003713</span></div>

2015-12-19T22:52:44Z

<span lang="EN-GB">Interleukin\r\n10 in lungs/small intestine for Bacterium pathway in co-infection (mouse):</span><div><span lang="EN-GB">UniProt AccessionID: </span><a href="http://www.uniprot.org/uniprot/P18893">P18893</a></div>

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Bb, MPI_Bacterium, Th1I_Bacterium in conjunction with Cb and IgG_Bacterium positively regulate AP [1]. Bb, MPI_Bacterium, Th1I_Bacterium in conjunction with AgAb_Bacterium positively regulate AP [1].

Bb, MPI_Bacterium, Th1I_Bacterium in conjunction with Cb and IgG_Bacterium or AgAb_Bacterium positively regulate AP [1].

Bb, MPI_Bacterium, Th1I_Bacterium in conjunction with Cb and IgG_Bacterium positively regulate AP [1].<div>"clearance in the lungs of co-infected hosts was similar to that observed in the single infection and driven by phagocytic cells activated by antibodies and Th1 cells" [1]</div>

Bb, MPI_Bacterium, Th1I_Bacterium in conjunction with Cb and IgG_Bacterium or AgAb_Bacterium positively regulate AP [1].

Bb, MPI_Bacterium, Th1I_Bacterium in conjunction with Cb and IgG_Bacterium or AgAb_Bacterium positively regulate AP [1].<div>"clearance in the lungs of co-infected hosts was similar to that observed in the single infection and driven by phagocytic cells activated by antibodies and Th1 cells" [1]</div>

Bb, MPI_Bacterium, Th1I_Bacterium in conjunction with Cb and IgG_Bacterium positively regulate AP [1].

Bb, MPI_Bacterium, Th1I_Bacterium in conjunction with AgAb_Bacterium positively regulate AP [1].<div>"clearance in the lungs of co-infected hosts was similar to that observed in the single infection and driven by phagocytic cells activated by antibodies and Th1 cells" [1]</div>

S_50 1 S_30 1 S_31 1 S_49 1 S_14 1 S_15 1 S_31 1 S_49 1 S_14 1

DCII_TRatearformis and IL12II and T0 in conjunction positively regulate Th1II_TRetortaeformis [1]

S_19 1 S_22 1 S_4 1 S_19 1

<div>DCII_Bacterium in conjunction with T0 and IL12II activate Th1II_Bacterium [1].</div><div><p class="MsoNormal" style="margin-bottom: 0.0001pt;"><br/></p></div>

DCII_Bacterium in conjunction with T0 and IL12II activate Th1II_Bacterium [1].

S_52 1 S_4 1 S_22 1

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 14.40000057220459px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">DCII_TRatearformis in conjunction with T0 positively regulates IL12II [1]. DCII_Bacterium and T0 in conjunction positively regulate IL2II [1]. IL4II negatively regulates IL12II [1].</span><div><br/></div>

<span style="orphans: 3; widows: 3;">"IL4 or IL12 can be produced by B. bronchiseptica- or T. retortaeformis-specific T subtypes or dendritic cells" [1]</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">"IL4 or IL12 can be produced by B. bronchiseptica- or T. retortaeformis-specific T subtypes or dendritic cells" [1]</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 14.40000057220459px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">DCII_TRatearformis in conjunction with T0 positively regulates IL12II [1]</span><div><span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 14.40000057220459px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">DCII_Bacterium and T0 in conjunction positively regulate IL2II [1]</span></div>

S_19 1 S_22 1 S_42 1 S_52 1 S_22 1 S_42 1

TrII positively regulates TrI_Bacterium [1].

TrII positively regulates TrI_Bacterium [1]

S_38 1

Th2II_Bacterium positively regulates Th2I_Bacterium [1].

Th2II_Bacterium positively regulates Th2I_Bacterium [1]

S_39 1

PIC activates NE_Bacterium [1].

PIC activates NE_Bacterium [1]

S_27 1

Bb in conjunction with either BC_Bacterium or IgA_Bacterium itself positively regulates IgA_Bacterium [1,2,3,4]

<span style="color: rgb(51, 51, 51); font-family: arial, sans-serif; line-height: 18.0049991607666px; background-color: rgb(255, 255, 255);"> "Activation of B cells by T helper cells led to the prompt increase of peripheral antibodies (serum IgG and IgA)" [1,2,3,4]</span>

Bb in conjunction with either BC_Bacterium or IgA_Bacterium itself positively regulates IgA_Bacterium [1]

S_8 1 S_14 1 S_10 1 S_14 1

PIC positively regulates DCI_TRetortaeformis [1].

<span style="color: rgb(51, 51, 51); font-family: arial, sans-serif; line-height: 18.0049991607666px; background-color: rgb(255, 255, 255);">"Both parasite stages activate epithelial cells that lead to the production of pro-inflammatory cytokines which then activate dendritic cells" [1]</span>

S_27 1

BC_Bacterium positively regulates itself [1]. T0 positively regulates BC_Bacterium [1].

BC_Bacterium positively regulates itself [1]

T0 positively regulates BC_Bacterium [1]

S_10 1 S_22 1

IS activates EC_TRetortaeformis [1]. AD activates EC_TRetortaeformis [1].

AD activates EC_TRetortaeformis [1]

<span style="orphans: 3; widows: 3;">IS activates EC_TRetortaeformis [1]</span>

S_33 1 S_21 1

MPI_Bacterium activates IFNg_Bacterium [1]. DCI_Bacterium activates IFNg_Bacterium [1]. Th1I_Bacterium positively regulates IFNg_Bacterium [1]. IL10I_Bacterium negatively regulates IFNg_Bacterium and is dominant over Th1I_Bacterium [1]. IL4I negatively regulates IFNg_Bacterium [1].

<span style="orphans: 3; widows: 3;">IL10I_Bacterium negatively regulates IFNg_Bacterium and is dominant over Th1I_Bacterium [1]</span>

<span style="orphans: 3; widows: 3;">MPI_Bacterium activates IFNg_Bacterium [1]</span>

<span style="orphans: 3; widows: 3;">Th1I_Bacterium positively regulates IFNg_Bacterium [1]</span><div><span style="orphans: 3; widows: 3;">IL10I_Bacterium negatively regulates IFNg_Bacterium and is dominant over Th1I_Bacterium [1]</span></div>

<span style="orphans: 3; widows: 3;">DCI_Bacterium activates IFNg_Bacterium [1]</span>

<span style="orphans: 3; widows: 3;">IL4I negatively regulates IFNg_Bacterium [1].</span>

S_51 1 S_49 1 S_40 1 S_53 1 S_31 1

Th2II_TRetortaeformis positively regulates Th2I_TRetortaeformis [1]

S_18 1

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Bb self regulates. PH negatively regulates Bb [1].</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">PH negatively regulates Bb [1].</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Bb self regulates [1].</span>

S_14 1 S_45 1

Bb in conjunction with either IgA_Bacterium or IgG_Bacterium positively regulates AgAb_Bacterium [1].

Bb in conjunction with IgG_Bacterium positively regulates AgAb_Bacterium [1].

Bb in conjunction with IgA_Bacterium positively regulates AgAb_Bacterium [1].

S_8 1 S_14 1 S_50 1 S_14 1

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255);">Bb activates TTSSI [1]. IgG_Bacterium inhibits TTSSI [1]. </span><span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255); font-size: 10pt;">IgA_Bacterium inhibits TTSSI [1].</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.40000057220459px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">IgG_Bacterium inhibits TTSSI [1].</span>

S_14 1 S_8 1 S_50 1

<div>IL5 in conjunction with IgE activates El2 [1]. IL5 in conjunction with IL13 activates El2 [1]. </div>

"The role of IL5 and IL13 is mostly in the recruitment of eosinophils" [1]

"The role of IL5 and IL13 is mostly in the recruitment of eosinophils" [1]<div>IL5 in conjunction with IgE activates El2 [1]</div>

IL5 in conjunction with IgE activates El2 [1]

S_37 1 S_34 1 S_25 1 S_34 1

DCII_TRetortaeformis and T0 in conjunction positively regulate Th2II_TRetortaeformis [1] IL12II negatively regulates Th2II_TRetortaeformis [1]

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);"> IL12II negatively regulates Th2II_TRetortaeformis [1]</span>

"<span style="color: rgb(51, 51, 51); font-family: arial, sans-serif; line-height: 18.0049991607666px; background-color: rgb(255, 255, 255);">Dendritic cells also activated the Th2 cell mediated expression of IL4</span>" [1]<div>"<span style="background-color: rgb(255, 255, 255); color: rgb(51, 51, 51); font-family: arial, sans-serif; line-height: 18.0049991607666px; font-size: 10pt;">dendritic cells interact with naïve T cells (T0) leading to the activation of T cell subtypes Th1 and Th2 through the production of IL12 and IL4</span><span style="font-size: 10pt;">" [1]</span></div>

"<span style="color: rgb(51, 51, 51); font-family: arial, sans-serif; line-height: 18.0049991607666px; background-color: rgb(255, 255, 255);">dendritic cells interact with naïve T cells (T0) leading to the activation of T cell subtypes Th1 and Th2 through the production of IL12 and IL4</span>" [1]

S_19 1 S_22 1 S_4 1

DCI_TRetortaeformis positively regulates DCII_TRetortaeformis [1].

S_9 1

Th1II_TRetortaeformis positively regulates Th1I_TRetortaeformis [1]

S_2 1

DCII_Bacterium positively regulates T0 [1]. DCII_TRatearformis positively regulates T0 [1].

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">DCII_Bacterium positively regulates T0 [1]</span>

DCII_TRatearformis positively regulates T0 [1].

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<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255);">Th2I_TRetortaeformis positively regulates Il10I [1]. </span><span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255);">IL10I_Bacterium positively regulates Il10I [1].</span>

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IFNgI positively regulates IFNgII [1]. IFNg_Bacterium positively regulates IFNgII [1].

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">IFNg_Bacterium positively regulates IFNgII [1]</span>

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IS in conjunction with EL positively regulate IL13 [1]. EL2 activates IL13 [1]. <span style="orphans: 3; widows: 3;">Th2I_TRetoraeformis activates IL13 [1,2,3,4,5,6,7,8]. </span><span style="orphans: 3; widows: 3;">Th2I_Bacterium activates IL13 [1,2,3,4,5,6,7,8].</span>

<span style="orphans: 3; widows: 3;">IS in conjunction with EL positively regulate IL13 [1]</span>

EL2 activates IL13 [1]

IS in conjunction with EL positively regulate IL13 [1].

<span style="orphans: 3; widows: 3;">IL13 is mediated by Th2I_Bacterium [1,2,3,4,5,6,7,8]</span>

<span style="orphans: 3; widows: 3;">IL13 is mediated by Th2I_TRetortaeformis</span><span style="orphans: 3; widows: 3;"> [1,2,3,4,5,6,7,8]</span>

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<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">EL positively regulates TEL [1]. EL2 positively regulates TEL [1].</span>

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<div>EC_Bacterium positively regulates PIC [1]. <span style="font-size: 10pt;">EC_TRetortaeformis positively regulates PIC [1]. </span><span style="font-size: 10pt;">AD positively regulates PIC [1]. </span><span style="font-size: 10pt;">AP positively regulates PIC [1]. IL10I negatively regulates PIC [1].</span><span style="font-size: 10pt;"> </span><span style="font-size: 10pt;">IgA_TRetortaeformis negatively regulates PIC [1].</span></div>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255);">AD positively regulates PIC [1]</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255);">IL10I negatively regulates PIC [1]</span>

"For example, pro-inflammatory cytokines are systematically detectable when any one of the parasites activates epithelial cells" [1]

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255);">IgA_TRetortaeformis negatively regulates PIC [1]</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255);">AP positively regulates PIC [1]</span>

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BC _TRetortaeformis positively regulates IgG [1].

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T0 positively regulates BC_TRetoraeformis [1]. BC_TRetortaeformis positively regulates BC_TRetoraeformis [1].

<span style="orphans: 3; widows: 3;">T0 positively regulates BC_TRetoraeformis [1]</span>

<span style="orphans: 3; widows: 3;">BC_TRetortaeformis positively regulates BC_TRetoraeformis [1].</span>

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AgAb_Bacterium in conjunction with IgG_Bacterium positively regulates Cb [1]. Bb positively regulates Cb [1]. Oag negatively regulates Cb in the presence of Bb [1].

"<span style="color: rgb(51, 51, 51); font-family: arial, sans-serif; line-height: 18.0049991607666px; background-color: rgb(255, 255, 255);"> IgG and bacteria complexes also induce complement fixation along with bacteria themselves" [1]</span>

"<span style="color: rgb(51, 51, 51); font-family: arial, sans-serif; line-height: 18.0049991607666px; background-color: rgb(255, 255, 255);">Activation of complement by bacteria is inhibited by O-antigen" [1]</span>

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<div>Bb in conjunction with PIC positively regulates MPI_Bacterium [1]. Bb in combination with IFNgI_Bacterium activates MPI_Bacterium [1].</div>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255);">Bb in conjunction with PIC positively regulates MPI_Bacterium [1]</span><div><span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255);">Bb in combination with IFNgI_Bacterium activates MPI_Bacterium [1]</span></div>

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IS activates EL [1,2]. EL2 negatively regulates EL [1].

<span style="orphans: 3; widows: 3;">IS activates EL [1,2]</span>

EL2 negatively regulates EL [1]

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<div>IS activates AD [1]. AD<span style="font-size: 10pt;"> activates AD [1]. NE_TRetortaeformis negatively regulates AD [1]. MPI_Bacterium </span><span style="font-size: 10pt;">negatively regulates AD [1]. IgG </span><span style="font-size: 10pt;">negatively regulates AD [1].</span></div>

AD activates AD [1]

IS positively regulates AD [1].

MPI_Bacterium negatively regulates AD [1]

NE_TRetortaeformis negatively regulates AD [1]

IgG negatively regulates AD [1]

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EL2 activates IL5 [1]. Th2II_TRetortaeformis activates IL5 [1,2,3,4,5,6,7,8]

EL2 activates IL5 [1]

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">IL5 is mediated by Th2II_TRetortaeformis [1,2,3,4,5,6,7,8]</span>

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Bb positively regulates Oag [1].

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NE_Bacterium positively regulates TNE [1]. NE_TRetortaeformis positively regulates TNE [1].

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">NE_TRetortaeformis positively regulates TNE [1]</span>

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<span style="orphans: 3; widows: 3;">BC in conjunction with IL13 positively regulate IgE [1]. BC in conjunction with IL4II positively regulate IgE [1].</span>

<span style="orphans: 3; widows: 3;">"The IgE isotype is produced upon signalling from either IL4 or IL13" [1]</span>

<span style="orphans: 3; widows: 3;">Naïve T cell-initiated B cell proliferation stimulated the prompt increase of mucus IgE [1]</span>

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<div>DCII_Bacterium in conjunction with T0 and TTSSII activate TrII [1].</div>

DCII_Bacterium in conjunction with T0 and TTSSII activate TrII [1].

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<div>DCII_Bacterium positively regulates Th2II_Bacterium [1]. <span style="font-size: 10pt;">T0 positively regulates Th2II_Bacterium [1]. IL2II negatively regulates Th2II_Bacterium [1].</span></div>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255);">DCII_Bacterium positively regulates Th2II_Bacterium [1]</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255);">IL2II negatively regulates Th2II_Bacterium [1]</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255);">T0 positively regulates Th2II_Bacterium [1]</span>

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TTSSI positively regulates TTSSII [1].

TTSSI positively regulates TTSSII [1]

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<div>DCII_TRatearformis in conjunction with T0 positively regulate IL4II [1]. <span style="font-size: 10pt;">DCII_Bacterium in conjunction with T0 positively regulate IL4II [1]. Th2II_Bacterium activates IL4II [1]. </span><span style="font-size: 10pt;">Th2II_</span>TRatearformis<span style="font-size: 10pt;"> activates IL4II [1]. IL12II negatively regulates IL4II [1]. IFNgI inhibits IL4II [1]. EL2 negatively inhibits IL4II [1].</span></div>

"IL4 or IL12 can be produced by B. bronchiseptica- or T. retortaeformis-specific T subtypes or dendritic cells" [1]

EL2 negatively inhibits IL4II [1]

" IL12 induced by bacterial factors can inhibit IL4 production by helminth-specific Th2 cells" [1]

"IL4 or IL12 can be produced by B. bronchiseptica- or T. retortaeformis-specific T subtypes or dendritic cells" [1]

IFNgI inhibits IL4II [1]

"IL4 or IL12 can be produced by B. bronchiseptica- or T. retortaeformis-specific T subtypes or dendritic cells" [1]<div>"IL4 is produced by T helper cells during T helper cell differentiation" [1]</div>

"IL4 or IL12 can be produced by B. bronchiseptica- or T. retortaeformis-specific T subtypes or dendritic cells" [1]

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NE_Bacterium positively regulates DP (DNE) [1]. TTSSI positively regulates DP (DNE) [1]

NE_Bacterium positively regulates DP (DNE) [1].

 TTSSI positively regulates DP (DNE) [1]

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PIC and AD in conjunction positively regulate NE_TRetortaeformis [1]. IFNgl positively regulates NE_TRetortaeformis [1]. IL4I and IL10l both independently negatively regulate NE_TRetortaeformis [1].

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">PIC and AD in conjunction positively regulate NE_TRetortaeformis [1]</span>

<span style="color: rgb(51, 51, 51); font-family: arial, sans-serif; line-height: 18.0049991607666px; background-color: rgb(255, 255, 255);">"IL4 and IL10, produced by Th2 cells, have anti-inflammatory properties and inhibit pro-inflammatory cytokines and neutrophils" [1]</span>

"<span style="color: rgb(51, 51, 51); font-family: arial, sans-serif; line-height: 18.0049991607666px; background-color: rgb(255, 255, 255);">neutrophils are recruited by pro-inflammatory cytokines and Th1 mediated IFN?</span>" [1]

"<span style="color: rgb(51, 51, 51); font-family: arial, sans-serif; line-height: 18.0049991607666px; background-color: rgb(255, 255, 255);">IL4 contributed to inhibit neutrophils (via the inhibition of the IL12 node</span>" [1]<div><span style="color: rgb(51, 51, 51); font-family: arial, sans-serif; line-height: 18.0049991607666px; background-color: rgb(255, 255, 255);">"IL4 and IL10, produced by Th2 cells, have anti-inflammatory properties and inhibit pro-inflammatory cytokines and neutrophils" [1]</span></div>

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AP in conjunction with Bb activates PH [1].

<span style="orphans: 3; widows: 3;">"The node “activated phagocytic cells” represents the outcome of the stimulation of neutrophils and macrophages by antibody-antigen complex and complement. These cells induce the node phagocytosis that depletes bacteria" [1]</span>

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Bb activates EC_Bacterium [1].

Bb activates EC_Bacterium [1]

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BC_TRetortaeformis in conjunction with IS positively regulates IgA_TRetortaeformis [1]. 

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<div>DCI_TRetortaeformis positively regulates IFNgI [1]. Th1I<span style="font-size: 10pt;">_TRetortaeformis positively regulates IFNgI [1]. IFNg_Bacterium</span><span style="font-size: 10pt;"> positively regulates IFNgI [1].</span></div>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255); font-size: 10pt;">IFNg_Bacterium</span><span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255); font-size: 10pt;"> positively regulates IFNgI [1]</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255);">Th1I</span><span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255); font-size: 10pt;">_TRetortaeformis positively regulates IFNgI [1]</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255);">DCI_TRetortaeformis positively regulates IFNgI [1]</span>

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Th1II_Bacterium positively regulates Th1I_Bacterium [1].

Th1II_Bacterium positively regulates Th1I_Bacterium [1]

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BC_Bacterium and IgG_Bacterium independently positively regulate IgG_Bacterium [1].

IgG_Bacterium positively regulates IgG_Bacterium [1].

BC_Bacterium positively regulates IgG_Bacterium [1].

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Bb in conjunction with IFNg_Bacterium positively regulates DCI_Bacterium [1]. Bb in conjunction with PIC positively regulates DCI_Bacterium [1].

Bb in conjunction with IFNg_Bacterium positively regulates DCI_Bacterium [1]

Bb in conjunction with PIC positively regulates DCI_Bacterium [1].

Bb in conjunction with PIC positively regulates DCI_Bacterium [1]<div><br/></div><div>Bb in conjunction with IFNg_Bacterium positively regulates DCI_Bacterium [1]</div>

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DCI_Bacterium positively regulates DCII_Bacterium [1].

DCI_Bacterium positively regulates DCII_Bacterium [1]

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MPI_Bacterium positively regulates IL10I_Bacterium [1]. TrI_Bacterium positively regulates IL10I_Bacterium [1]. Th2I_Bacterium and TTSSI act in conjunction to positively regulate IL10I_Bacterium [1].

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">MPI_Bacterium positively regulates IL10I_Bacterium [1]</span>

"<em style="color: rgb(51, 51, 51); font-family: arial, sans-serif; line-height: 18.0049991607666px; background-color: rgb(255, 255, 255);">B. bronchiseptica</em><span style="color: rgb(51, 51, 51); font-family: arial, sans-serif; line-height: 18.0049991607666px; background-color: rgb(255, 255, 255);"> has been suggested to induce IL10 production by T cell subtypes" [1]</span>

"<span style="color: rgb(51, 51, 51); font-family: arial, sans-serif; line-height: 18.0049991607666px; background-color: rgb(255, 255, 255);">T regulatory (Treg) cells are stimulated by the type III secretion system of </span><em style="color: rgb(51, 51, 51); font-family: arial, sans-serif; line-height: 18.0049991607666px; background-color: rgb(255, 255, 255);">B. bronchiseptica</em><span style="color: rgb(51, 51, 51); font-family: arial, sans-serif; line-height: 18.0049991607666px; background-color: rgb(255, 255, 255);"> to produce IL10" [1]</span>

"<span style="color: rgb(51, 51, 51); font-family: arial, sans-serif; line-height: 18.0049991607666px; background-color: rgb(255, 255, 255);">By explicitly including the bacteria mediated up-regulation of IL10, through the type III secretion system (TTSS) modulation of T regulatory cells (Treg), we were able to capture the establishment of the bacteria in the lungs followed by their immune-mediated reduction and clearance" [1]</span>

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